Substituted propane-phosphinic acid compounds

ABSTRACT

Compounds of the formula I ##STR1## wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms, and wherein one of the groups R 1 , R 2  and R 3  represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another one of R 1 , R 2  and R 3  is hydrogen or, in the case of R 1  and R 2 , is hydroxy, and the remaining one of R 1 , R 2  and R 3  is hydrogen, and their salts have GABA B  -antagonistic properties and can be used as GABA B  -antagonists. They are obtained when in a compound of formula II ##STR2## in which R, R 1 , R 2  and R 3  have their previous significances, Z represents --NH 2  and R 4  denotes a hydroxy-protective group R 5  or, when R 1  and R 3  denote hydrogen and R 2  denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R 6 , or Z represents a protected or latent amino group Z 0  and R 4  deontes hydrogen or a hydroxy-protective group R 5 , any group R 5  or R 6  is replaced by hydrogen, and/or any group Z 0  is converted into --NH 2 .

This is a continuation-in-part application of our co-pending patentapplication Ser. No. 275,882, filed November 25, 1988 abandoned.

The invention relates to compounds of the formula I ##STR3## wherein Rdenotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic oraraliphatic radical having 2 or more carbon atoms, and wherein one ofthe groups R¹, R² and R³ represents hydrogen or an aliphatic,cycloaliphatic, araliphatic or aromatic radical, another one of R¹, R²and R³ is hydrogen or, in the case of R¹ and R² is hydroxy, and theremaining one of R¹, R² and R³ is hydrogen, and to theirpharmaceutically acceptable salts for use for the treatment of the humanor animal body, to pharmaceutical compositions containing the same andto compounds of the formula I, with the proviso that R is different from1,1-di(C₁ -C₄ -alkoxy)C₁ -C₅ alkyl, if one of R¹, R³ representshydrogen,. C₁ -C₈ -alkyl, C₃ -C₆ -cycloalkyl, phenyl optionallysubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/ortrifluoromethyl or C₇ -C₁₀ -phenylalkyl optionally substituted in thephenyl moiety by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/ortrifluoromethyl and the other two of R¹, R² and R³ are hydrogen, andwith the additional proviso that R is different from ethyl if R²represents hydroxy and R¹ and R³ are hydrogen, and to their salts,provided that salts of compounds of the formula I, wherein R denotes anunsubstituted aliphatic, cycloaliphatic or araliphatic hydrocarbonradical, R¹ and R₃ denote hydrogen and R² is hydrogen or alkyl, withbases are different from alkali metal and ammonium salts, and to aprocess for their manufacture.

Aliphatic radicals R are, for example, alkyl groups that may beinterrupted by one or two mutually spaced atoms selected from oxygen andsulfur and/or substituted by halogen or hydroxy, such as alkyl, alkylmono-, dior poly- substituted by halogen and/or hydroxy, alkyl beinginterrupted by one or two mutually spaced atoms selected from oxygen andsulfur or alkyl being interrupted by one or two mutually spaced atomsselected from oxygen and sulfur and substituted by halogen and/orhydroxy, alkenyl groups that may be mono-, di- or poly- substituted byhalogen and/or hydroxy, such as lower alkenyl or lower alkenylsubstituted by halogen and/or hydroxy, or alkynyl groups, such as loweralkynyl. Aliphatic radicals R₁, R₂ or R₃ are, for example, lower alkylgroups.

Cycloaliphatic radicals R are, for example, cycloalkyl groups that maybe interrupted by one or two mutually spaced atoms selected from oxygenand sulfur and/or substituted by hydroxy, such as cycloalkyl, cycloalkylbeing interrupted by one or two mutually spaced atoms selected fromoxygen and sulfur or cycloalkyl substituted by hydroxy. Cycloaliphaticradicals R₁, R₂ or R₃ are, for example, cycloalkyl groups.

Cycloaliphatic-aliphatic radicals R are, for example, cycloalkyl-loweralkyl groups that may be interrupted by one or two mutually spaced atomsselected from oxygen and sulfur and/or substituted by hydroxy and/orlower alkylthio, such as cycloalkyl-lower alkyl, cycloalkyl-lower alkylbeing interrupted by one or two mutually spaced atoms selected fromoxygen and sulfur or cycloalkyl-lower alkyl substituted in thecycloalkyl moiety by hydroxy or lower alkylthio and/or in the alkylenemoiety by hydroxy.

Araliphatic radicals R and/or R₁, R₂ or R₃ are, for example,phenyl-lower alkyl or naphthyl-lower alkyl radicals that may besubstituted in the aryl ring by halogen, lower alkyl, lower alkoxyand/or trifluoromethyl and/or in the lower alkylene moiety by hydroxy,such as phenyl-lower alkyl, phenyl-(1-hydroxy)-lower alkyl,naphthyl-lower alkyl or phenyllower alkyl substituted in the phenylmoiety by halogen, lower alkyl, lower alkoxy and/or trifluoromethyl.

Aromatic radicals R₁, R₂ or R₃ are, for example, phenyl, naphthyl orphenyl substituted by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl.

In compounds of formula I the group R is bonded to the P-atom via acarbon atom.

Alkyl, alkenyl and alkynyl R may contain up to and including 14,preferably 12 carbon atoms and are represented by lower alkyl, loweralkenyl and lower alkynyl. Alkyl R may also be a C₈ -C₁₄ -, e.g. a C₈-C₁₂ -alkyl, such as an octyl, nonyl, decyl, undecyl or dodecyl group,e.g. a decyl or dodecyl group.

Alkyl or alkenyl mono-, di- or poly- substituted by halogen and/orhydroxy is represented by mono- or dihydroxy-lower alkyl, hydroxy-loweralkenyl, mono-, di- or polyhalogeno-lower alkyl, mono-, di- orpolyhalogeno-lower alkenyl, mono-, di- or polyhalogeno-lowerhydroxyalkyl and mono-, di- or polyhalogeno-lower hydroxyalkenyl.

Alkyl being interrupted by one or two atoms selected from oxygen andsulfur is represented by lower alkoxy-lower alkyl, lower alkylthio-loweralkyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-loweralkyl, lower alkoxy-lower alkoxy-lower alkyl, di-lower alkoxy-loweralkyl, di-lower alkylthio-lower alkyl, and lower alkoxy-loweralkylthiolower alkyl.

Alkyl being interrupted by one or two atoms selected from oxygen andsulphur and substituted by hydroxy and/or halogen is represented bylower alkoxy-(hydroxy)lower alkyl and lower alkoxy-(halogeno)loweralkayl.

Cycloalkyl is represented by C₃ -C₈ -cycloalkyl.

Cycloalkyl substituted by hydroxy is represented by 1-hydroxy-C₃ -C₈-cycloalkyl.

Cycloalkyl and cycloalkyl in cycloalkyl-lower alkyl, in either case,being interrupted by one or two atoms selected from oxygen and sulfur isrepresented by oxa-C₃ -C₈ -cycloalkyl, thia-C₃ -C₈ -cycloalkyl, dioxa-C₃-C₈ -cycloalkyl, dithia-C₃ -C₈ -cycloalkyl and oxathia-C₃ -C₈-cycloalkyl.

Cycloalkyl-lower alkyl substituted in the cycloalkyl moiety by hydroxyand/or lower alkylthio and/or in the alkylene moiety by hydroxy isrepresented by lower alkylthiocycloalkyl-lower alkyl,cycloalkyl(hydroxy)lower alkyl and loweralkylthiocycloalkyl-(hydroxy)lower alkyl.

The general definitions used herein have the following meaning withinthe scope of the present invention.

The term "lower" referred to above and hereinafter in connection withorganic radicals or compounds respectively, if not defined explicitlyotherwise, defines such with up to and including 7, preferably up to andincluding 4, carbon atoms.

Lower alkyl R is represented by C₂ -C₇ -alkyl, especially by C₃ -C₇-alkyl, e.g. propyl, isopropyl, butyl, isobutyl, sec.-butyl,tert.-butyl, (2-methyl)butyl, hexyl or heptyl. Lower alkyl other than Rdenotes, for example, C₁ -C₄ -alkyl, e.g. methyl, ethyl, propyl,isopropyl, butyl or tert.-butyl.

Lower alkenyl denotes, for example, C₃ -C₇ -alkenyl, preferably C₃ -C₅alkenyl, carrying the double bond in a higher than the α,β-position, andis e.g. 2-propenyl (allyl), but-3-en-1-yl, (2-methyl)prop-2-en-1-yl(isobutenyl) or (5-methyl)but-2-en-1-yl, but may also carry the doublebond in α,β-position and may be, for example, vinyl, prop-1-enyl orbut-1-enyl, or may be a C₆ - or C₇ -alkenyl, such as a hexenyl orheptenyl, group.

Lower alkynyl denotes, for example, C₃ -C₇ -alkynyl, preferably C₃ -C₅-alkynyl, carrying the triple bond in a higher than the α,β-position andis e.g. 2-propynyl (propargyl), but-3-yn-1-yl, but-2-yn-1-yl orpent-3-yn-1-yl.

C₃ -C₈ -Cycloalkyl preferably has 3 to 6 ring carbon atoms and thus isC₃ -C₆ -cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

C₃ -C₈ -Cycloalkyl-lower alkyl preferably has 3 to 6 ring and 1 to 4chain carbon atoms and is, for example, C₃ -C₆ -cycloalkyl-C₁ -C₄-alkyl, such as cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl.

Mono- or dihydroxy-lower alkyl preferably carries one of the hydroxygroups in α-position and is for example, α-hydroxy-C₂ -C₇ -alkyl, suchas α-hydroxy-C₂ -C₄ -alkyl, e.g. 1-hydroxyethyl, 2-(2-hydroxy)propyl,1hydroxybutyl, 2-(2-hydroxy)butyl or 1-(1-hydroxy-2-methyl)propyl, orα,β-dihydroxy-C₂ -C₇ -alkyl, such as 1,2-dihydroxy-prop-2-yl, but mayalso carry a single hydroxy group in a higher than the α-position anddenote, for example, β-, γ- or δ-hydroxy-C₂ -C₇ -alkyl, e.g.3-hydroxypropyl or 2-, 3-or 4-hydroxybutyl.

Hydroxy-lower alkenyl preferably carries the hydroxy group in α-positionand the double bond in a higher than the α,β-position and is, forexample, corresponding α-hydroxy-C₃ -C₅ -alkenyl, e.g.1-hydroxybut-2-enyl.

Mono-, di- or polyhalogeno-lower alkyl is for example, mono-, di- ortrifluoro-C₂ -C₅ -alkyl, e.g. 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1,1-difluorobutyl.

Mono-, di- or polyhalogeno-lower alkenyl is, for example, mono-, di- ortrifluoro-C₃ -C₅ -alkenyl, e.g. 2-fluorobut-2-enyl.

Mono-, di- or polyhalogeno-lower hydroxyalkyl and mono-, di- orpolyhalogeno-lower hydroxyalkenyl preferably carries the hydroxy groupin α-position and the halogen atom(s) in a higher than the α-positionand is, for example, corresponding mono-, di- or trifluoro-α-hydroxyC₂-C₇ -alkyl or mono- di- or trifluoro-C₃ -C₇ -alkenyl, e.g.2-fluoro-1-hydroxy-butyl, 2-fluoro-1-hydroxy-but-2-en-1-yl or4,4,4-trifluoro-1-hydroxy-butyl.

Lower alkoxy-lower alkyl preferably has up to 10 carbon atoms and is,for example, C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl, such as C₁ -C₃ -alkoxy-C₁ -C₃-alkyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxypropyl or 1- or 2-methoxybutyl.

Lower alkoxy is, for example, C₁ -C₄ -alkoxy, e.g. methoxy, ethoxy,isopropoxy, propoxy, butoxy, sec.-butoxy or tert.-butoxy.

Lower alkoxy-lower alkoxy-lower alkyl is, for example, C₁ -C₄ -alkoxyC₂-C₄ -alkoxy-C₁ -C₄ -alk yl, e.g. 2-methoxyethoxymethyl.

Lower alkylthio-lower alkyl preferably has up to 10 carbon atoms and is,for example, C₁ -C₄ -alkylthio-C₁ -C₄ -alkyl, such as C₁ -C₃-alkylthio-C₁ -C₃ -alk yl, e.g. methylthiomethyl, ethylthiomethyl,2-methylthioethyl, 2-ethylthioethyl or 3-methylthiopropyl.

Lower alkansulfinyl- and lower alkanesulfonyl-lower alkyl preferably hasup to 10 carbon atoms and is, for example, C₁ -C₄ -alkanesulfinyl- or C₁-C₄ -alkanesulfonyl-C₁ -C₄ -alkyl, e.g. ethanesulfinylmethyl orethanesulfonylmethyl.

Di-lower alkoxy-lower alkyl preferably has up to 15 carbon atoms totallyand is, for example, di-C₁ -C₄ -alkoxy-C₁ -C₃ -alkyl, such as di-C₁ -C₃-alkoxy-C₁ -C₃ -alkyl, e.g. dimethoxymethyl, diethoxymethyl,dipropyloxymethyl, 1,1- or 2,2-diethoxyethyl, diisopropyloxymethyl,di-n-butoxymethyl or 3,3-dimethoxypropyl.

Di-lower alkylthio-lower alkyl preferably has up to 15 carbon atomstotally and is, for example, di-₁ -C₄ -alkylthio-C₁ -C₄ -alkyl, such asdi-C₁ -C₃ -alkylthio-C₁ -C₃ -alkyl, e.g. dimethylthiomethyl,diethylthiomethyl or 1,1-or 2,2-dimethylthioethyl.

Lower alkoxy-(hydroxy)lower alkyl is, for example C₁ -C₄ -alkoxy-C₁ -C₇-(hydroxy)alkyl e.g. 2-(2-hydroxy-3-methoxy)propyl.

Lower alkoxy-(halogeno)lower alkyl is, for example C₁ -C₄ -alkoxy-C₁ -C₇-(halogeno)alkyl e.g. 1-(2-fluoro-1-methoxy)butyl.

Hydroxy-C₃ -C₈ -cycloalkyl is, for example, 1-hydroxy-C₃ -C₆-cycloalkyl, e.g. 1-hydroxycyclobutyl.

Oxa- or thia-C₃ -C₈ -cycloalkyl preferably has 2 to 6 ring carbon atomsis, for example, 2-oxacyclopropyl (oxiranyl), 2- or 3-oxacyclobutyl(oxetanyl), 2- or 3-thiacyclobutyl (thietanyl), 2- or 3-oxacylcopentyl(tetrahydrofuranyl), 2- or 3-thiacyclopentyl (thiolanyl) or2-oxacyclohexyl (tetrahydropyranyl).

Dioxa-C₃ -C₈ -cycloalkyl preferably has 3 to 5 ring carbon atoms andcarries those two oxygen atoms in 1,3-position to each other, andrepresents e.g. 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

Dithia-C₃ -C₈ -cycloalkyl preferably has 3 to 5 ring carbon atoms andcarries those two sulfur atoms in 1,3-position to each other andrepresents e.g. 1,3-dithiolan-2-yl or 1,3-dithioxan-2-yl. Oxathio-C₃ -C₈-cycloaklyl is, for example 1,3-oxathiolan-2-yl or 1,3-oxathioxan-2-yl.

C₃ -C₈ -Cycloalkyl-(hydroxy)lower alkyl preferably has 3 to 6 ring and 1to 4 chain carbon atoms and is, for example, cyclo-C₃ -C₆ -alkyl-C₁ -C₄-alkyl, e.g. 1-cyclopropyl-1-hydroxymethyl or1-hydroxy-1-cyclobutylmethyl. Lower alkylthiocycloalkyl-(hydroxy) loweralkyl is, for example, 1-hydroxy1-(2-methylthiocyclopropyl).

Halogen, as a substituent of aromatic and/or araliphatic radicals R¹, R²or R³, is preferably chloro, but may also be fluoro, bromo or iodo.

A phenyl or naphthyl group may have one or more than one, preferably oneor two of the same or different substituents as defined hereinbefore.Phenyl- or naphthyl-lower alkyl is e.g. benzyl, naphth-2-ylmethyl, 1- or2-phenylethyl or 2- or 3-phenylpropyl, each optionally substituted asdescribed hereinbefore.

Salts of the compounds of the formula I are particularlypharmaceutically acceptable salts thereof, such as the correspondingaddition salts with acids, as well as the salts with bases. Suitableacids for the formation of acid addition salts are, for example, mineralacids, such as hydrochloric, hydrobromic, sulphuric or phosphoric acid,or organic acids, such as organic sulphonic acids, for example,benzenesulphonic, 4-toluenesulphonic or methanesulphonic acid, andorganic carboxylic acids, such as acetic, lactic, palmitic, stearic,malic, maleic, fumaric, tartaric, ascorbic or citric acid. Salts withbases are, for example, alkali metal or alkaline earth metal salts, suchas sodium, potassium, calcium or magnesium salts, or ammonium salts,such as those with ammonia or suitable organic amines, e.g.diethylamine, di-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine.The compounds of the formula I may also form inner salts.

Depending on the presence of asymmetric carbon atoms, the compounds ofthis invention may be in the form of mixtures of isomers, particularlyracemates, or in the form of pure isomers, particularly opticalantipodes. Compounds of the formula I, wherein R denotes an 1,1-di(C₁-C₄ -alkoxy)C₁ -C₅ alkyl group, one of R:, R and R: denotes hydrogen, C₁-C₈ -alkyl, C₃ -C₆ -cycloalkyl, phenyl optionally substituted byhalogen, C₁ -C₄ -alkyl, C₁ -C₄ alkoxy and/or trifluoromethyl or C₇ -C₁₀-phenylalkyl optionally substituted in the phenyl moiety by halogen, C₁-C₄ -alkyl, C₁ -C₄ -alkoxy and/or trifluoromethyl and the other two arehydrogen, are known as intermediates for the preparation ofcorresponding compounds, wherein R denotes hydrogen, and of their salts.Also, salts of those compounds of the formula I, wherein R denotes ahydrocarbon radical, R₁ and R₃ denote hydrogen and R₂ denotes hydrogenor alkyl, are known and have been proposed as flame-protective andsurface-active agents.

However, compounds of formula I wherein R denotes 1,1-di(C₁ -C₄-alkoxy)C₁ -C₅ -alkyl, one of R¹ and R² represents hydroxy and R³ andthe other one of R¹ and R² are hydrogen, the specific compounds offormula I, wherein R is diethoxymethyl, one of R¹ and R² isp-chlorophenyl or methyl and the other one and R³ are hydrogen, andcompounds of the formula I, wherein R

is a group of the formula --CH(OR')₂ in which R' represents C₁ -C₄-alkyl, such as isopropyl or n-butyl, and R¹, R² and R³ are hydrogen,and their salts are hitherto not described in the art and are thusconsidered novel.

The invention therefore relates also to those generically andspecifically novel compounds generically known as intermediates and totheir pharmaceutically acceptable salts for use in the treatment of thehuman or animal body and to pharmaceutical preparation containing thesame, as well as to compounds of formula I, wherein R is diethoxymethyl,one of R¹ and R² is p-chlorophenyl or methyl and the other one and R³ ishydrogen, or wherein R is a group of the formula --CH(OR')₂ in which R'represents C₁ -C₄ -alkyl, such as ethyl, propyl, isopropyl or n-butyl,and R¹, R² and R³ denote hydrogen, and to their salts.

It has now been found that the compounds of the formula I and theirpharmaceutically acceptable salts possess valuable pharmacologicalproperties. They show an effective binding at the GABA_(B) -receptor andare found to act as antagonists on said receptor. Mechanistically,antagonism at GABA_(B) receptors may increase the release of fastexcitatory amino acid transmitters, i.e glutamate and aspartate, thusimproving information processing in the brain. In line with this is thefinding that the late inhibitory postsynaptic potential in hippocampus,attributed to a GABA_(B) mechanism, is shortened by the antagonists thusallowing a faster sequence of nerve impulse transfer.

On the other hand, chronic treatment with antidepressants and repetitiveelectroshock have been found to increase the number of GABA_(B)receptors in rat cerebral cortex. In line with receptor theories,chronic treatment with GABA_(B) antagonists should result in the sameeffect. For these and other reasons, GABA_(B) antagonists may thereforeact as antidepressants.

The GABA_(B) antagonists of the present invention interact at theGABA_(B) receptor with IC₅₀ values starting from about 10⁻⁷ M(moles/liter) in rat brain cortex membranes. In contrast to GABA_(B)agonists, such as baclofen, they do not potentiate the stimulation ofadenylate cyclase in rat cerebral cortex slices by noradrenaline, butantagonize the effects of baclofen. The antagonism against baclofen hasalso been shown in in vitro electrophysiological models, such as thepenicilline-induced "epileptic" hippocampal slice preparation, wherebaclofen, at a concentration of 6 μM inhibits "epileptic"-likedischarges of pyramidal cells. The compounds of the invention antagonisethe effects of baclofen at concentrations from approximately 10 toapproximately 100 μM. In vivo, antagonism has been shown by ionophoresisof baclofen on rat cerebral cortex, and systemic application ofantagonists in doses of 10-100 mg/kg. The muscle relaxant effects ofbaclofen measured in the rotarod model are also antagonized at doses ofabout 30 mg/kg ip.

The antagonists do not only show antagonistic effects against baclofen,but have, as theoretically expected (see above), also effects on theirown as antagonists of endogenous GABA. Thus the antagonists are activein behavioural models which are established in the art to bs indicativeof antidepressant, anxiolytic and/or nootropic properties. Compounds ofthe formula I have been found to be active, after peroral application,in the swim test according to Porsolt, in the Geller test, the onetrial, step-down passive avidance test (one-trial modification) inpretrial and posttrial situations, in the two compartment test and inthe complex labyrinth. In addition, in studies on Rhesus monkeys, anincrease in playfulness, exploration, social grooming and a reduction ofsigns of anxiety were observed. Accordingly, the compounds of formula Imay be used as nootropic, antidepressive and anxiolytic agents. Ofcourse, they may also be used as baclofen-antidotes.

The invention relates in particular to compounds of the formula I,wherein R has 2 or more carbon atoms and denotes alkyl, alkenyl,alkynyl, alkyl or alkenyl mono-, di- or poly-substituted by halogenand/or hydroxy, alkyl being interrupted by one or two mutually spacedatoms selected from oxygen and sulfur, alkyl being interrupted by one ortwo mutually spaced atoms selected from oxygen and sulfur andsubstituted by halogen and/or hydroxy, cycloalkyl, cycloalkylsubstituted by hydroxy, cycloalkyl being interrupted by one or twomutually spaced atoms selected from oxygen and sulfur, cycloalkyl-loweralkyl, cycloalkyl-lower alkyl substituted in the cycloalkyl moiety byhydroxy or lower alkylthio and/or in the alkylene moiety by hydroxy,kcycloalkyl-lower alkyl being interrupted by one or two mutually spacedatoms selected from oxygen and sulfur in the cycloalkyl moiety,phenyl-lower alkyl, naphthyl-lower alkyl phenyl- or naphthyl lower alkylring substituted by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl or naphthyl-lower alkyl, and/or chain-substituted byhydroxy and wherein one of the groups R¹, R² and R³ represents hydrogen,lower alkyl, cycloalkyl, phenyl or naphthyl, phenyl or naphthylsubstituted by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, phenyl-lower alkyl or phenyl lower alkyl substituted inthe phenyl moiety by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, another one of R¹, R² and R³ is hydrogen or, in thecase of R¹ and R², is hydroxy and the remaining one of R¹, R² and R³ ishydrogen, and to their salts, especially pharmaceutically acceptablesalts, with the provisos given hereinbefore.

The invention relates, for example, to compounds of the formula I,wherein R has 2 or more carbon atoms and is lower alkyl, lower alkenyl,lower alkynyl, alkyl being interrupted by one or two mutually spacedatoms selected from oxygen, sulfur and cycloalkyl, cycloalkyl beinginterrupted by one or two mutually spaced atoms selected from oxygen andsulfur, cycloalkyl or cycloalkyl-lower alkyl being interrupted by one ortwo mutually spaced atoms selected from oxygen and sulfur in thecycloalkyl moiety; and wherein one of the groups R¹, R² and R³represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenyl substitutedby halogen, lower alkyl, lower alkoxy and/or trifluoromethyl, phenyllower alkyl or phenyl lower alkyl substituted in the phenyl moiety byhalogen, lower alkyl, lower alkoxy and/or trifluoromethyl, or one of R¹and R² is hydroxy; and the remaining two of R¹, R² and R³ are hydrogen,and to their salts, especially pharmaceutically acceptable salts, withthe provisos given hereinbefore.

The invention relates, above all, to compounds of the formula I, whereinR has 2 or more carbon atoms and is lower alkyl, lower alkenyl, loweralkynyl, a cycloalkyl, hydroxycycloalkyl, cycloalkyl-lower alkyl,cycloalkyl-(hydroxy)lower alkyl or loweralkylthiocycloalkyl-(hydroxy)lower alkyl group having 3 to 6 ring carbonatoms, mono- or dihydroxylower alkyl, hydroxy-lower alkenyl, mono-, di-or polyhalogeno-lower alkyl, mono-, di-or polyhalogeno-lower alkenyl,mono-, di- or polyhalogeno-(hydroxy)lower lower alkyl, mono-, di- orpolyhalogeno-(hydroxy)lower alkenyl, lower alkoxy-lower alkyl, loweralkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl, loweralkanesulfonyl-lower alkyl, di-lower alkoxy-lower alkyl, di-loweralkylthio-lower alkyl, lower alkoxy(hydroxy)lower alkyl, loweralkoxy-(halogeno)lower alkyl, phenyl-lower alkyl, phenyl-lower alkylmono- or disubstituted, in the phenyl moiety, by halogen, lower alkyl,lower alkoxy and/or trifluoromethyl, naphthyllower alkyl, oxa- orthiacycloalkyl having 2 to 6 ring carbon atoms, or dioxa-, oxathia- ordithiacycloalkyl having 3 to 5 ring carbon atoms, and wherein one of R¹,R², R³ represents hydrogen, lower alkyl, cycloalkyl having 3 to 6 ringcarbon atoms, phenyl, phenyl mono- or disubstitued by halogen, loweralkyl, lower alkoxy and/or trifluoromethyl, phenyl-lower alkyl orphenyl-lower alkyl mono- or disubstitued by halogen, lower alkyl, loweralkoxy and/or trifluoromethyl, another one of R¹, R² and R³ is hydrogenor, in the case of R¹ and R², is hydroxy; and the remaining one of R¹,R² and R³ is hydrogen, and to their salts, especially pharmaceuticallyacceptable salts, with the provisos given hereinbefore.

One embodiment of the invention consists of the sub-group A of compoundsof formula I, wherein R has 2 or more carbon atoms and is lower alkyl,lower alkenyl, lower alkynyl, a cycloalkyl, hydroxycycloalkyl,cycloalkyl-lower alkyl, cycloalkyl-(hydroxy)lower alkyl or loweralkylthiocycloalkyl-(hydroxy)lower alkyl group having 3 to 6 ring carbonatoms, hydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- orpolyhalogenolower alkyl, mono-, di-or polyhalogeno-lower alkenyl, mono-,di-or polyhalogeno-(hydroxy)lower alkyl, mono-, di- orpolyhalogeno-(hydroxy)lower alkenyl, phenyl-lower alkyl phenyl-loweralkyl mono- or disubstituted, in the phenyl moiety, by halogen, loweralkyl, lower alkoxy and/or trifluoromethyl or naphthyl-lower alkyl, andwherein one of the groups R¹, R² and R³ represents hydrogen, loweralkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl,lower alkoxy and/or trifluoromethyl, phenyl lower alkyl or phenyl loweralkyl substituted in the phenyl moiety by halogen, lower alkyl, loweralkoxy and/or trifluoromethyl, another one of R¹, R² and R³ is hydrogenor, in the case of R¹ and R² is hydroxy; and the remaining one of R¹, R²and R³ is hydrogen, and their salts, especially pharmaceuticallyacceptable salts.

Compounds of subgroup A are, for example, those, wherein R has 2 or morecarbon atoms and is, lower alkenyl or lower alkynyl, and wherein one ofthe groups R¹, R² and R³ represents hydrogen, lower alkyl, cycloalkyl,phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, phenyl lower alkyl or phenyl lower alkyl substituted inthe phenyl moiety by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, or one of R¹ and R² is hydroxy; and the remaining twoof R¹, R² and R³ are hydrogen, and their salts, especiallypharmaceutically acceptable salts.

Another embodiment of the invention consists of the subgroup B of thecompounds of formula I, wherein R is represented by lower alkoxy-loweralkyl, lower alkylthio-lower alkyl, lower alkanesulfinyl-lower alkyl,lower alkanesulfonyl-lower alkyl, di-lower alkoxy-lower alkyl, di-loweralkylthio-lower alkyl, lower alkoxy-(hydroxy)lower alkyl, loweralkoxy-(halogeno)lower, oxa- or thiacycloalkyl having 2 to 6 ring carbonatoms, or dioxa- or dithiacycloalkyl having 3 to 5 ring carbon atoms,and wherein one of the groups R¹, R² and R³ represents hydrogen, loweralkyl, cycloalkyl, phenyl, phenyl substituted by halogen, lower alkyl,lower alkoxy and/or trifluoromethyl, phenyl lower alkyl or phenyl loweralkyl substituted in the phenyl moiety by halogen, lower alkyl, loweralkoxy and/or trifluoromethyl, another one of R¹, R² and R³ is hydrogenor, in the case of R and R:, is hydroxy; and the remaining one of R¹, R²and R³ is hydrogen, provided that, if one of R¹ and R² is hydrogen,lower alkyl, cycloalkyl, phenyl, phenyl substituted by halogen, loweralkyl, lower alkoxy and/or trifluoromethyl, phenyl-lower alkyl orphenyl-lower alkyl substituted in the phenyl moiety by halogen, loweralkyl, lower alkoxy and/or trifluoromethyl, and the other two of R¹, R²and R³ are hydrogen, R is different from 1,1-di(C₁ -C₄ -alkoxy)-C₁ -C₅-alkyl, and their salts, especially pharmaceutically acceptable salts,with the provisos given hereinbefore.

Compounds of subgroup B are, for example, those, wherein R isrepresented by lower alkoxy-lower alkyl, lower alkylthio-lower alkyl,di-lower alkoxy-lower alkyl, di-lower alkylthio lower alkyl, loweralkoxy-lower alkylthio-lower alkyl, oxacycloalkyl, thiacycloalkyl,dioxacycloalkyl and dithiacycloalkyl, and wherein one of the groups R¹,R² and R³ represents hydrogen, lower alkyl, cycloalkyl, phenyl, phenylsubstituted by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, phenyl lower alkyl or phenyl lower alkyl substituted inthe phenyl moiety by halogen, lower alkyl, lower alkoxy and/ortrifluoromethyl, or one of R¹ and R² is hydroxy; and the remaining twoof R¹, R² and R³ are hydrogen, and their salts, especiallypharmaceutically acceptable salts, with the provisos given hereinbefore.

Preferred are compounds of formula I, wherein R has the meaning definedhereinbefore, and wherein one of the groups R¹, R² and R³ representshydrogen, lower alkyl, phenyl or phenyl substituted by halogen or loweralkyl, and the remaining two of R¹, R² and R³ are hydrogen, and theirsalts, especially pharmaceutically acceptable salts.

Further preferred are compounds of formula I, wherein R is lower alkylhaving 2 or more carbon atoms, lower alkenyl or lower alkynyl, R²represents hydrogen, lower alkyl, phenyl or phenyl substituted byhalogen or lower alkyl and R¹ and R² are hydrogen, and pharmaceuticallyacceptable salts thereof.

Equally preferred is the subgroup B' of compounds of the formula I,wherein R is lower alkoxy-lower alkyl or mono- or dihydroxy-lower alkyl,R² represents hydrogen, lower alkyl, phenyl or phenyl substituted byhalogen or lower alkyl and R¹ and R² are hydrogen, with the provisosgiven hereinbefore and pharmaceutically acceptable salts thereof.

The invention relates especially to compounds of the formula I, whereinR is C₂ -C₁₂ -alkyl, such as ethyl, butyl, isobutyl, pentyl orisopentyl, C₂ -C₇ -alkenyl, such as but-3-enyl, C₂ -C₇ -alkynyl, such aspent-3-ynyl, mono- or dihydroxy-C₂ -C₇ -alkyl, such as2-(2-hydroxy)propyl, 2-(1,2-dihydroxy)propyl. 2-(2-hydroxy)butyl or1-hydroxybutyl, mono-, di- or trihalogeno-o-hydroxy-C₃ -C₇ -alkyl, suchas 1-hydroxy-4,4,4-trifluorobutyl, α-saturated mono-, di- ortrihalogeno-α-hydroxy-C₃ -C₇ -alkenyl, ' such as1-hydroxy-2-fluoro-but-2-enyl, C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl, such as2-ethoxyethyl, di-C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl, such as diethoxymethyl,α-hydroxy-C₃ -C₆ -cycloalkyl, such as 1-hydroxycyclobutyl, C₃ -C₆-cycloalkyl-C₁ -C₄ alky yl, such as cyclopropylmethyl, C₃ -C₆-cycloalkyl-α-hydroxyC₁ -C₃ -alkyl, such as1-cyclobutyl-1-hydroxymethyl, or 1-C₁ -C₄-alkylthiocycloalkyl-α-hydroxy-C₁ -C₄ -alk yl, such as(1-methylthiocyclopropyl)(1-hydroxy)methyl, R² represents hydrogen,hydroxy, C₁ -C₄ -alkyl, such as methyl, phenyl or phenyl substituted byhalogen, such as chloro, or C₁ -C₄ -alkyl, such as methyl and R¹ and R²are hydrogen or one of R¹ and R² denotes hydroxy and the other one aswell as R³ represents hydrogen, and to their salts, especiallypharmaceutically acceptable salts, with the provisos given hereinbefore.

Even more preferred are subgroups A' and/or B' of compounds of formulaI, wherein R either is C₂ -C₇ -alkyl, C₂ -C₇ -alkenyl or C₂ -C₇ -alkynylor denotes C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl or di-C₁ -C₄ -alkoxy-C₁ -C₄-alkyl or denotes α-, β-, γ- or δ-hydroxy-C₂ -C₇ -alkyl orα,β-dihydroxy-C₂ -C₇ -alkyl, R² represents hydrogen, lower alkyl, phenylor phenyl substituted by halogen or lower alkyl, and R¹ and R² arehydrogen, with the provisos given hereinbefore, and pharmaceuticallyacceptable salts thereof, with the provisos given hereinbefore.

Especially preferred are compounds of the formula I, wherein R denotesC₂ -C₇ -alkyl, such as ethyl, butyl, isobutyl, pentyl or isopentyl,α-saturated C₃ -C₇ -alkenyl, such as but-3-enyl, α-saturated C₃ -C₇-alkynyl, such as pent-3-ynyl, α-, β-, γ- or 4-hydroxy-C₂ -C₄ -alkyl,such as 2-(2-hydroxy)propyl or 1-hydroxybutyl, α,β-dihydroxy-C₂ -C₄-alkyl, such as 2-(1,2-dihydroxy)propyl, mono-, di- ortrifluoro-α-hydroxy-C₃ -C₇ - alkyl, such as1-hydroxy-4,4,4-trifluorobutyl, α-saturated mono-, di- ortrihalogeno-α-hydroxy-C₃ -C₇ -alkenyl, such as1-hydroxy-2-fluorobut-2-enyl, C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl, such as2-ethoxyethyl, diC₁ -C₄ -alkoxy-C₁ -C₄ - alkyl, C₃ -C₆ -cycloalkyl-C₁-C₄ -alkyl, such as cyclopropylmethyl, α-hydroxy-C₃ -C₆ -cycloalkyl,such as 1-hydroxycylobutyl, or C₃ -C₆ -cycloalkyl-α-hydroxy-C₁ -C₄-alkyl, such as 1-cyclopropyl-1-hydroxymethyl, and R¹, R² and R³represent hydrogen, and to their salts, especially pharmaceuticallyacceptable salts.

Very especially preferred are subgroups A and/or B of compounds offormula I, wherein R is C₂ -C₇ -alkyl, C₂ -C₇ -alkenyl or C₂ -C₇-alkynyl, or C₁ -C₄ -alkoxy-C₁ -C₄ -alkyl or di-C_(-alkoxy-C) ₁ -C₄-alkyl and R¹, R² and R³ are hydrogen, and pharmaceutically acceptablesalts thereof, with the provisos given hereinbefore.

Most preferred is subgroup(s) A and/or B compounds of formula I, whereinR is C₃ -C₇ -alkyl and R¹, R² and R³ are hydrogen, and pharmaceuticallyacceptable salts thereof.

The invention specifically relates to compounds of the formula Idescribed in the Examples herein, and to their salts, especiallypharmaceutically acceptable salts.

Although salts of compounds of the formula I are included in the abovedefinitions of preferred compounds, the invention predominantly relatesto the free compounds of formula I.

The process for the manufacture of compounds of the formula I, ischaracterized in that

(a) in a compound of formula II ##STR4## in which R¹, R², R³ and R⁴ havetheir previous significances, Z represents --NH₂ and R⁴ denotes ahydroxy-protective group R⁵ or, when R¹ and R³ denote hydrogen and R²denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R⁶,or Z represents a protected or latent amino group Z^(o) and R⁴ denoteshydrogen or a hydroxy-protective group R⁵, any group R⁵ or R⁶ isreplaced by hydrogen and/or any group Z^(o) is converted into --NH₂ ; or

(b) in a compound of the formula III ##STR5## ' in which R, R¹ and R²have their previous significances and X is a group capable of beingconverted into a group of formula --CH(R³)NH₂, the group X is convertedinto a group of formula wherein R³ has its previous significance; or (c)a compound of formula I', said compound of formula I' being otherwiseidentical to a compound of formula I but having one or morecarbon-carbon-multiple bond(s) is reduced to produce a compound offormula I, and, if desired, a resulting salt obtained in this processmay be converted into the free compound or into another salt and/or, ifdesired, a resulting free compound is converted into a salt to suit theabove definition and/or, if desired, a resulting mixture of isomers isseparated into the individual isomers.

Protected hydroxy groups such as groups --OR⁵ present in a protectedform in starting materials of the formula II are, for example,etherified hydroxy groups, such as hydroxy groups etherified withaliphatic, cycloaliphatic or araliphatic alcohol, e.g. with a loweralkanol, a cycloalkanol, or a phenyl- or diphenyl-lower alkanol, orhydroxy groups etherified with an aliphatic silanol, e.g. with atri-lower alkyl silanol. As groups R⁵ O--, lower alkoxy, e.g. C₁ -C₄-alkoxy, mono- or diphenyl-lower alkoxy, e.g. 1-phenyl- or1,1-diphenyl-C₁ -C₄ -alkoxy, and tri-lower alkylsilyloxy, e.g. tri-C₁-C₄ -alkyl-, such as trimethylsilyloxy, are especially preferred.

Protected amino groups Z^(o) in starting materials of the formula IIare, for example, acylamino groups such as lower alkanoylamino, e.g.acetylamino, or phthalimido, lower alkoxycarbonylamino unsubstituted orsubstituted by phenyl, e.g. benzyloxycarbonylaminp ortert-butoxycarbonylamino groups, or 1-aryl-methylamino groups e.g.benzylamino, or 1-phenyl-lower alkylamino, silylated amino groups, suchas tri-lower alkylsilylamino or especially bis-(tri-loweralkylsilyl)amino, e.g. bis trimethyl silylamino. A latent amino groupZ^(o) may be e.g. nitro or azido.

Preferred compounds of formula II are those having the formula IIa##STR6## wherein R⁵ represents a hydroxy-protective group, for example,C₁ -C₄ -alkyl or C₁ -C₄ -alkyl substituted by lower alkanoyloxy or byone or two optionally substituted phenyl groups, such as 1-C₂ -C₇-alkanoyloxyC₁ -C₄ -alkyl, e.g. pivaloyloxymethyl, or 1-phenyl- or1,1-diphenyl-C₁ -C₄ -alkyl e.g. benzyl, or having the formula IIb##STR7## wherein R⁵ represents a hydroxy-protective group, for example,C₁ -C₄ -alkyl, C₁ -C₄ -alkyl substituted by one or two optionallysubstituted phenyl groups, such as 1-phenyl- or 1,1-diphenyl-C₁ -C₄-alkyl, e.g. benzyl, or a silyl group, such as tri-C₁ -C₄ -alkylsilyl,e.g. trimethylsilyl, and Z^(o) has its previous significance anddenotes, for example, C₁ -C₇ -alkanoylamino, e.g. acetylamido,phthalimido or bis-silylamino, such as bis(tri-C₁ -C₄ -alkylsilyl)amino,e.g. bis(trimethylsilyl)amino, or having the formula IIc ##STR8##wherein Z^(o) has its previous significance and denotes, for example, C₁-C₇ -alkanoylamino, e.g. acetylamino, C₁ -C₄ -alkoxycarbonylamino, e.g.tert.-butyloxycarbonylamino, or phenyl-C₁ -C₄ -alkoxycarbonylamino, orhaving the formula ##STR9## wherein R⁶ denotes an alkalimetal orammonium ion, and wherein in formulae IIa, IIb and IIc R, R¹, R² and R³have their previous significance or in formula IId R denotes anunsubstituted aliphatic, cycloaliphatic or araliphatic hydrocarbonresidue, R¹ and R² represent hydrogen and R² denotes hydrogen or alkyl.

The replacement of the protective group R⁵ in compounds of formula II,IIa or IIb by hydrogen may be effected by treatment with a suitablenucleophilic reagent such as an alkali metal hydroxide, e.g. sodiumhydroxide, or lithium hydroxide, an alkali metal halide, particularlybromide or iodide such as lithium bromide or sodium iodide, thiourea, analkali metal thiophenolate such as sodium thiophenolate. The replacementreaction may be carried out in the absence or presence of a solvent and,if necessary, while cooling or heating, in a closed vessel and/or underan atmosphere of an inert gas.

When R⁵ denotes C₁ -C₄ -alkyl substituted in 1-position by one or twophenyl groups, e.g. when R⁵ is benzyl, the replacement of such a groupin compounds of formulae II, IIa or IIb by hydrogen may be effected byhydrogenolysis in the presence of a metallic hydrogenation catalyst, orany other suitable procedure.

Alternatively, the replacement of the protective group, e.g. of a silylor alkyl group, R⁵ in compounds of formulae II, IIa or IIb or of analkalimetal or ammonium ion R⁵ in compounds of the formulae II or IId byhydrogen may be effected by treatment with an acid under hydrolyticconditions, especially with a mineral acid such as a hydrohalic acide.g. hydrochloric acid which is used in dilute or concentrated aqueousform, or by treatment with an organic silyl halide such astrimethylsilyl iodide or bromide, followed by hydrolysis, if necessary.The reaction is preferably conducted at elevated temperature e.g. whilerefluxing the reaction mixture and, if necessary using an organicdiluent, in a closed vessel and/or under an atmosphere of an inert gas.The kind of replacement of the protective group R⁵ depends e.g. on thesubstituent R present in a compound of formula II which must be retainedin converting a compound of formula II to a compound of formula I. Saidreplacement may be effected e.g. according to the illustrating examples.

Protected amino group or latent amino groups Z^(o) in compounds offormula II, IIb or IIc may be converted into free amino according toknown methods, which are selected according to the characteristics ofthe protected or latent amino group to be converted into amino, such assolvolytic or hydrogenolytic procedures, for example, hydrolysis in thepresence of an acid or a base, acidolysis, e.g. treatment withtrifluoroacetic acid, treatment with hydrazine, or hydrogenolysis in thepresence of a metallic hydrogenation catalyst, or any other suitableprocedure. Depending on the groups involved, the replacement andconversion operations may be carried out in any sequence orsimultaneously by methods which are well known per se.

It is preferred that all protecting groups are converted, R⁵ or R⁶ beingconverted to H and Z^(o) being converted to NH₂, in a single step, bytreatment with an acid, preferably a hydrohalic acid, especiallyhydrochloric acid, under hydrolytic conditions.

The compounds of formula II may be prepared, for example, by variousmethods according to the nature of the group X in the formula V definedhereinafter, e.g. by reacting, in the presence of a basic catalyst or inthe presence of agents forming free radicals, a compound of the formula(IV) ##STR10## in which R and R⁴ have their previous significance whichcan be prepared by reaction of a compound of the formula R-PHal₂ (IVa;Hal=halogen) with an alcohol R⁵ OH in the presence of a tri-loweralkylamine or, more advantageously, by reaction of aqueoushypophosphorous acid with an orthoester of the formula C(C₁ -C₄-alkyl)(OR⁵)₃ (Ivb) yielding, in the latter case, a compound IV, whereinR denotes C(C₁ -C₄ -alkyl)(OR⁵)₂, with a compound of formula V ##STR11##22 in which R¹ and R² have their previous significance and X is a groupcapable of being converted into a group of formula --CH(R³)--Z, whereinR³ and Z have their previous significances, in order to produce acompound of formula VI ##STR12## wherein R¹, R², R⁴, R and X have theirprevious significances; and then converting the group X into a group offormula --CH(R³)--Z.

A group X is primarily cyano but may also represent carbamoyl, a groupof formula --CH(R³)--Z^(o) (VIa) in which R³ and Z^(o) have theirprevious significance; or X is a group of formula --C(R³)=Y in which R³has its previous significance and --C=Y is an optionally functionallymodified carbonyl group such as a corresponding ketal or thioketalgroup, including a corresponding cyclic group.

When, in a compound of formula IV R⁴ has its previous significance and,in the compound of formula V, X is an activating group Xa such as cyanoor --C(R³)=O, then either a basic catalyst or a free radical catalystmay be employed. When, however, the same compounds of formula IV arereacted with compounds of formula V in which X is e.g. a residue offormula-- CH(R³)--Z^(o), then free radical catalysts are required.

A basic catalyst used in the first step may be e.g. an alkali metal C₁-C₄ -alkoxide, for example, a sodium or potassium C₁ -C₄ -alkoxide, inparticular sodium methoxide, sodium ethoxide or potassium tert-butoxide,an alkaline or alkaline earth metal fluoride, such as potassium fluorideor caesium fluoride, or an alkali metal hydride, such as sodium hydride.The reaction may be effected with or without the use of an addedsolvent. If a solvent is added, this is preferably an alcohol, inparticular a C₁ -C₄ -alkanol corresponding to the alkoxide used as basiccatalyst. The reaction temperature may vary from 0° C. to the boilingpoint of any added solvent.

Agents forming free radicals are, for example, compound convertible intofree radicals by ionizing or ultra-violet radiation, preferably peroxycompounds, such as inorganic peroxy compounds, e.g. hydrogen peroxide orammonium persulfate, or organic peroxides, e.g. benzoyl peroxide ortert-butyl peroxide, or organic azo compounds, e.g.azo-bis-isobutyronitrile. Reactions involving free radical-formingagents may be conducted in the optional presence of a solvent and, ifnecessary, while cooling or heating, in a closed vessel and/or in anatmosphere of an inert gas.

The conversion of a group X into the group --CH(R³)--Z is carried outaccording to known methods. Cyano and carbamoyl are converted intoaminomethyl by reduction, cyano, for example, by hydrogenation in thepresence of a suitable catalyst, e.g. Raney nickel and of a solvent,such as ethanol, which may preferably contain ammonia, and carbamoyl,for example, by treatment with a suitable hydride reducing agent, suchas borane in tetrahydrofuran.

The conversion of a group X in the compounds of formula VI in which X isa group --C(R³)=Y, in which Y is oxygen, into the group of the formula--CH(R³)--Z is carried out by known reductive amination procedures, e.g.treatment with sodium cyanoborohydride in the presence of ammoniumacetate in a suitable solvent, such as dioxane, and while cooling, e.g.at about 0° C.

The compounds of formula IV are either known or they may be prepared bymethods as described hereinbefore. Specific examples of compounds offormula IV include: iso-propyl (ethyl)phosphonite, isopropyl(n-propyl)phosphonite, iso-butyl (n-butyl)phosphonite, iso-butyl(iso-propyl)phosphonite, iso-butyl (iso-butyl)phosphonite and iso-butyl(sec.-butyl)phosphonite.

Likewise, compounds of formula V are either known or can be obtained bymethods which are well known.

Alternatively, a compound of the formula VII ##STR13## in which R⁵ is C₁-C₄ alkyl or C₁ -C₄ -alkyl substituted by one or two phenyl residues oran additional group --Si(R⁷)₃, each R⁷, independently, is C₁ -C₆ -alkyl,preferably C₁ -C₂ -alkyl, particularly methyl, the groups R⁵ and R⁷being the same or different, can be reacted with a compound of theformulae ##STR14## in which R¹, R², R³, Z^(o) and X have their previoussignificances, X being primarily cyano or a group of the formula--C(R³)=Y and Hal stands for halogen, such as iodo, bromo or chloro. Thereaction with an epoxide of formula VIIIb is advantageously carried outin the presence of a mild Lewis acid, such as anhydroux zinc chloride,whilst the reactions with halides of formulae VIIIa or VIIIc arepreferably carried out under the conditions of the Arbusov method, e.g.at a reaction temperature ranging from room temperature to an elevatedtemperature, e.g. 160° C., while removing the trialkyl silyl halideformed in the reaction.

The compounds of formula IIb and/or IIc may also be prepared startingfrom and reacting, e.g. acylating a compound of formula IX ##STR15##wherein R¹, R² and R³ have their previous significances to give acompound of formula X ##STR16## wherein R¹, R² and R³ have theirprevious significance and Z^(o) is an e.g. acylated amino group and,subsequently, protecting the (acid) hydroxyl group in the compound offormula X to produce a compound of formula XI ##STR17## wherein R¹, R²,R³ and Z^(o) have their previous significances and R⁵ O denotesprotected, e.g. esterified, hydroxy. Alternatively, the startingmaterial of formula IX can be reacted with a silylating agent, such as ahexa-lower alkyl silazane or a tri-lower alkyl halogenosilane, e.g. withhexamethyldisilazane, or with trimethylchlorsilane in the presence oftriethylamine, to produce a compound of formula ##STR18## wherein R⁵ ₀ agroup R⁵ being denotes tri-lower alkylsilyl, e.g. trimethylsilyl, andZ^(o) denotes bis(tri-lower alkylsilyl)amino, such asbis(trimethylsilylamino).

The intermediate of the formula XI or XI' is then reacted with acompound capable of converting the ##STR19## group into a ##STR20##wherein R has its previous significance to produce a compound of formulaIIb, in which R⁵ has its previous significance. Thus, the intermediateof the formula XI may be reacted, in the presence of a basiccondensation agent, such as a tri-lower alkyl amine, e.g. ofN-ethyl-N,N-diisopropyl-amine, with a corresponding halide, e.g. a loweralkyl halide the formula R-Hal (XIIc, Hal=halogen), preferably underbasic conditions, or may be reacted, for the manufacture of compoundsIIb, in which R is an aliphatic, cycloaliphatic-aliphatic or araliphaticradical having at least 2 carbon atoms in each of the aliphaticmoieties, in which radical R the carbon atom via which R is bonded tothe P-atom is unsubstituted and the adjacent carbon atom is notsubstituted by hydroxy or, in the case of aliphatic radicals R, byhalogen or, in the case of cycloaliphatic-aliphatic radicals R, by loweralkylthio, with a terminally unsaturated aliphatic,cycloaliphatic-aliphatic or araliphatic compound R"'-H (XIIb), whereinR"' is a group otherwise identical to the radical R in the desired endproduct IIb but has one additional terminal double bond between thecarbon atom via which R is bonded to the P-atom and the adjacent carbonatom, or may be reacted, for the manufacture of compounds IIb, in whichthe carbon atom via which R is bonded to the P-atom is substituted byone hydroxy group, with an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic aldehyde or ketone (XIIa), whichcompound XIIa corresponds, if the aldehyde or ketone functional group isreplaced by one free valence and one hydroxy group, to the group R inthe desired end product IIb.

The starting materials of formula IX and their production have beendescribed in U.S. Pat. No. 4656298 which discloses the replacement, in acompound of formula XIII' ##STR21## wherein one of R¹ _(a), R² _(a) andR³ _(a) is hydrogen, C₁ -C₈ -alkyl, C₃ -C₆ -cycloalk yl, phenyloptionally substituted by halogeno, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/orCF₃, or is C₇ -C₁₀ -phenylalkyl optionally substituted in the phenylmoiety by halogeno, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/or CF₃, and theother two are hydrogen, Z^(o) ' is a protected amino group, R⁵ _(a) ishydrogen, C₁ -C₄ -alkyl or an alkali metal or ammonium cation and Q ishydrogen or a protecting group,

replacing to group R⁵ _(a), when it is alkyl, by hydrogen or by analkali metal or ammonium cation; replacing the group Q when it is aprotecting group, by hydrogen; and converting Z^(o) _(a) into NH₂, toproduce a compound of formula IX.

In U.S. Pat. No. 4656298, protecting groups Q e.g. --C(C₁ -C₄-alkyl)(OR^(a))(OR^(b)), preferably --CH(OR^(a))(OR^(b)) in which R^(a)and R^(b) are C₁ -C₄ -alkyl, especially --CH(OC₂ H₅)₂ and/or a C₁ -C₄-alkyl group R⁵ _(a), may be replaced by hydrogen by treating thecompound of formula XIII' with an acid under hydrolytic conditions; orby treatment with an organic silyl halide such as trimethyl silyl iodideor bromide, followed by hydrolysis. It is preferred in U.S. Pat. No.2656298, to replace protecting groups Q and R⁵ _(a) by hydrogen, andconvert Z^(o) _(a) into NH₂ in compounds of formula XIII', in a singlestep, with an acid under hydrolytic conditions.

This known method has the disadvantage that, under the drastic reactingconditions disclosed, the hydroxy-protecting group R⁵ _(a) and theaminoprotecting group are removed simultaneously with the protectinggroup Q.

It has now been found that in a compound of formula XIII or XIV##STR22## wherein R¹, R², R³, R⁵, Q, X and Z^(o) have their previoussignificance, the respective protecting groups R⁵ and Z^(o), or R⁵ andX, respectively, are retained, when the compound of formula XIII or XIVis treated with a protic anhydrous medium, to produce a compound offormula XI, or a compound of formula ##STR23##

Examples of such protic anhydrous media include:

anhydrous hydrogen chloride gas, or an anhydrous medium may be generatedfrom an organic compound having one or more Si-Cl bonds together with anagent e.g. an alkanol capable of cleaving the Si-Cl bond, to produce ananhydrous protic medium in situ.

Preferred anhydrous protic media include therefore trimethyl silylchloride in technical chloroform which contains ethanol.

This novel route has the advantage that re-protecting steps, e.g. IX→Xand X→XI, necessary for known routes, are avoided.

The invention, therefore, also relates to a process for the manufactureof compounds of the formula ##STR24## wherein X denotes cyano, carbamoylor a group of the formulae --CH(R³)Z^(o) (Xva) or --C(R³)=Y (XVb) inwhich Z^(o) denotes a protected or latent amino group as specifiedhereinbefore, Y denotes an optionally acetalised, thioacetalised,ketalised or thioketalised oxo group, one of R¹, R² and R³ is hydrogen,hydroxy, C₁ -C₈ -alkyl, C₃ -C₆ -cycloalkyl, phenyl optionallysubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/ortrifluoromethyl or is C₇ -C₁₀ -phenylalkyl optionally substituted in thephenyl moiety by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and/ortrifluoromethyl and the others of R¹, R² and R³ are hydrogen, and R⁵_(b) denotes a C₁ -C₄ -alkyl radical, characterised in that a compoundof the formula ##STR25## wherein R¹, R², R³, R⁵ _(b) and X have themeanings given hereinbefore and Q' denotes a group of the formula--C(R⁸)--C(OR⁹)(OR¹⁰) (XIVa) in which R⁸ denotes lower alkyl and R⁹ andR¹⁰, independently of one another, represent lower alkyl or togetherrepresent lower alkylene, is treated with an anhydrous protic medium,and to compounds of formula XV, whenever manufactured by this process oran obvious chemical equivalent thereof.

The novel process is carried out at a temperature ranging from -80° C.to 100° C., preferably from 0° C.-50° C.

While the relative molar ratios of the reactants i.e. of reactant XIV tothe organic silyl chloride, used may vary within a wide range, it ispreferred to use molar ratios ranging from 1 to 2 molar equivalents ofthe latter, per molar equivalent of XIV.

In a preferred embodiment of process variant (a) for the manufacture ofcompounds of formula I a compound of the formula IIa ##STR26## whereinR⁵ denotes lower alkyl and R, R¹, R² and R³ have their previoussignificances which may be obtained, for example, according to thereaction sequences

    IV+V→VI→IIa;

    VII+vIIIc→

    VI→IIa;

    VII+VIIIb→(IIb)→IIa or

    XIV→XV→VI→IIa;

is subjected to basic or acidic hydrolysis or is treated with atri-lower alkyl halogenosilane.

The combined process characterised by the reaction sequence

    XIV→XV→VI→IIa→I

is a novel and advantageous route to compounds of formula I.

The invention, therefore also relates to a process for the manufactureof compounds of the formula I ##STR27## wherein R denotes an aliphatic,cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2or more carbon atoms, and wherein one of the groups R¹, R² and R³represents hydrogen or an aliphatic, cycloaliphatic, araliphatic oraromatic radical, another one of R¹, R² and R³ is hydrogen, or in thecase of R¹ and R², is hydroxy, and the remaining one of R¹, R² and R³ ishydrogen, and to their salts, characterised in that a compound of theformula ##STR28## wherein R⁵ _(b) denotes a C₁ -C₄ -alkyl radical, Xdenotes cyano, carbamoyl or a group of the formulae --CH(R³)--Z^(o)(Xva) or --C(R³)=Y (Xvb) in which Z^(o) denotes a protected or latentamino group as specified hereinbefore, Y denotes an optionallyacetalised, thioacetalised, ketalised or thioketalised oxo group and Q'denotes a group of the formula --C(R⁶)(OR⁹)(OR¹⁰) (XIVa) in which R⁸denotes lower alkyl and R⁹ and R¹⁰, independently of one another,represent lower alkyl or together represent lower alkylene and R¹, R²and R³ have the meanings given hereinbefore, is treated with ananhydrous protic medium, the resulting compound of the formula ##STR29##wherein R¹, R², R⁵ _(b) and X have their previous significances isreacted with an aldehyde or ketone XIIa or with a compound of theformulae R"'-H (XIIb) or R-Hal (XIIc) wherein Hal R and R"', and thecompound XIIa have their previous significances, in the resultingcompound of formula VI ##STR30## wherein R¹, R², R⁵ _(b), R and X havetheir previous significances; the group X is converted into a group offormula --CH(R³)--NH₂ (IIa') and the resulting compound of formula IIa##STR31## wherein R, R¹, R², R³ and R⁵ _(b) have their previoussignificances is converted into the corresponding compound of formula I.

In this context, X is preferably cyano, the anhydrous protic medium ispreferably generated from trimethylsilychloride and commercial-gradechloroform, the intermediate Xv is preferably reacted with a compoundXIIc and/or the conversion of the cyano group into the --CH₂ NH₂ groupis preferably effected by hydrogenolysis.

In another preferred embodiment of process variant (a), a compound ofthe formula IIc ##STR32## wherein R, R¹, R², R³, R⁵ and Z^(o) have theirprevious significances, which may be prepared, for example, via thereaction sequences

    IX→X→XI→IIb or

    IX→XI'→IIb,

is subjected to basic or acidic hydrolysis or is treated with atri-lower alkyl halogenosilane followed by aqueous workup.Advantageously, a compound IIb, wherein R⁵ denotes tri-lower alkylsilyl,Z^(o) denotes bis(lower alkylsilyl)amino and R¹, R² and R³ have theirprevious significances, is formed in situ by reacting a compound of theformula ##STR33## with a silylating agent and subsequently, preferablyunder basic conditions, with a compound of the formula R-Hal (XIIb;Hal=halogen) and de-protected according to the invention, when worked upunder protic, e.g. aqueous or aqueous/alcoholic conditions.

The conversion of the group X into a group of formula --CH(R³)--NH₂according to process variant b) may be effected by any of the methodsdescribed hereinbefore, e.g. by a variation of the conversion ofcompounds of formula VI into compounds of formula II.

The reaction is carried out according to known methods, in the absenceor presence of a solvent, which may also serve as a reagent, ifnecessary, while cooling or heating, in a closed vessel and/or in theatmosphere of an inert gas.

The starting materials of the formula III may be prepared, for example,from compounds of the formula VI by converting the group R⁵ O- intohydroxy, the reaction being carried out according to the previouslydescribed procedure, e.g. by acidic hydrolysis, such as by treatmentwith an aqueous mineral acid, e.g. hydrochloric acid, or by treatmentwith a nucleophilic reagent.

In process variant (c), a compound of formula I' may have itsunsaturation within the substituent R such that it is e.g. of theformula I" ##STR34## In this case R^(IV) may be selected from loweralkenyl, lower alkanedienyl or lower alkynyl, to produce a compound offormula I, wherein R is lower alkyl, or phenyl to produce a compound offormula I wherein R is cyclohexyl.

The reduction may be effected by any suitable reducing agent, such ashydrogen in the presence of a catalyst, for the reduction of aryl e.g.Nishimura catalyst and for the reduction of aliphatic multiple bondse.g. Palladium on charcoal, in the presence or absence of a solvent andat room temperature or elevated temperature.

The compounds of formula I' may be produced according to any of themethods described herein for the manufacture of compounds of formula Istarting from starting materials having the respective unsaturatedsubstituents. Furthermore, compounds of formula I" may also be obtainedstarting from the corresponding R^(IV) -dichlorophosphine by reactionwith lower alkanol, such as ethanol, and a tri-lower alkylamine, such astriethylamine, reacting the resulting R^(IV) -phosphonous acid esterwith a compound of formula HC(R¹)=C(R²)--X (V; X=e.g. CN) and convertingthe group X into the corresponding group --CH(R³)--NH₂.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures preferably nearthe boiling point of the solvents used, at atmospheric orsuperatmospheric pressure.

Compounds of the formula I obtainable according to the process of theinvention may be interconverted into another.

Thus, compounds of formula I, wherein R is substituted by hydroxy,and/or R¹ or R² denotes hydroxy, can be converted into the correspondinghydroxy-free compounds, for example, by reacting withthiocarbonyldiimidazole and treating the resultingimidazolylthiourethane in the presence of a radical-initiator, such asazoisobutyronitrile, with a tri-lower alkylstannane, e.g. with (C₄ H₉)₃SnH, for example in benzene at 60 to 80° C.

Also double and/or triple bonds present in the group R may be reduced tosingle bonds, triple bonds also to double bonds to yield thecorresponding less unsaturated compound of formula I.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed under the reaction conditions, or inwhich the reaction components are used in the form of their salts oroptically pure antipodes. Whenever desirable, the above processes arecarried out after first suitably protecting any potentially interferingreactive functional groups, e.g. as illustrated herein.

Advantageously, those starting materials should be used in saidreactions that lead to the formation of those compounds indicated aboveas being preferred.

The invention also relates to novel starting materials and processes fortheir manufacture. Thus, compounds of formula IIa and IIc except those,wherein R¹ and R³ denote hydrogen, R² is hydrogen or alkyl and R denotesan unsubstituted aliphatic cycloaliphatic or araliphatic radical, or oneof R¹, R² and R³ represents hydrogen or an aliphatic, cycloaliphatic,araliphatic or aromatic radical and the other two of R¹, R² and R³denote hydrogen and R is --CH(O--C₁ -C₄ alkyl)₂ or --C(C₁ -C₄-alkyl)(O--C₁ -C₄ alkyl) ₂ and compounds of formula IIb except those inwhich one of R¹, R² and R³ represents hydrogen or an aliphatic,cycloaliphatic, araliphatic or aromatic radical and the other two of R¹,R² and R³ denote hydrogen and R is --CH(O--C₁ -C₄ alkyl)₂ or --C(C₁ -C₄alkyl)(O--C₁ -C₄ alkyl).sub. 2, are n ew. Those new compounds formfurther aspects of the invention.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers, forexample, as diastereomers, as optical isomers (antipodes), as racemates,or as mixtures thereof.

In case diastereomeric mixtures of the above compounds or intermediatesare obtained, these can be separated into the single racemic oroptically active isomers by methods in themselves known, e.g. byfractional distillation, crystallization or chromatography.

The racemic products of formula I or basic intermediates can be resolvedinto the optical antipodes, for example, by separation of diastereomericsalts thereof, e.g., by the fractional crystallization of d- orl-(tartrate, dibenzoyltartrate, mandelate or camphorsulfonate) salts.

Advantageously, the more active of the antipodes of the compounds ofthis invention is isolated. Furthermore, the compounds of the inventionare either obtained in the free (Zwitterion-) form, or as a saltthereof. For example, any resulting free compound can be converted intoa corresponding acid addition salt, preferably with the use of apharmaceutically acceptable acid or anion exchange preparation, saltswith bases by treatment of the free compounds with bases or suitablecation exchange techniques, or resulting salts can be converted into thecorresponding free compounds, for example the acid addition salts, withthe use of a stronger base, such as a metal or ammonium hydroxide, orany basic salt, e.g., an alkali metal hydroxide or carbonate, or acation exchange preparation and the salts with bases by treatment withsuitable acidic reagents. These or other salts, for example, thepicrates, can also be used for purification of the compounds obtained;the compounds are then first converted into salts. In view of the closerelationship between the free compounds and the compounds in the form oftheir salts, whenever a compound is referred to in this context, acorresponding salt is also intended, provided such is possible orappropriate under the circumstances and the term "salts" shall, ifdesired also include the free compounds, where appropriate according tomeaning and purpose.

The compounds, including their salts, may also be obtained in the formof their hydrates, or include other solvents used for thecrystallization.

The present invention also relates to the use of the compounds of theinvention for the preparation of pharmaceutical compositions, especiallypharmaceutical compositions having selective GABA_(B) -antagonisticactivity which can be used for the treatment of e.g. cognitive andmemory disorders, depressive states of mind and anxieties.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, for the treatment of diseasesresponsive to GABA_(B) -receptor blocking as given above, comprising aneffective GABA_(B) -receptor blocking amount of a compound of theinvention, alone or in combination with one or more pharmaceuticallyacceptable carriers.

The pharmacologically active compounds of the invention are incorporatedinto pharmaceutical compositions comprising an effective amount thereofin conjunction or admixture with excipients or carriers suitable foreither enteral or parenteral application.

Preferred are tablets and gelatin capsules comprising the activeingredient together with (a) diluents, e.g. lactose, dextrose, sucrose,mannitol, sorbitol, cellulose and/or glycine; (b) lubricants, e.g.silica, talcum, stearic acid, its magnesium or calcium salts and/orpolyethylene glycol; for tablets also (c) binders, e.g. magnesiumaluminum silicate, starch paste, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired,(d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or (e) absorbents, colourants, flavoursand sweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously preparedfrom fatty emulsions or suspensions. Said compositions may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, the compositions may also containother therapeutically valuable substances. Said compositions areprepared according to conventional mixing, granulating or coatingmethods, respectively, and contain about 0.1 to 75%, preferably about 1to 50%, of the active ingredient.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. Characteristically,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound, optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

The present invention also relates to the use of compounds of theinvention having GABA_(B) -antagonistic properties and pharmaceuticalcompositions comprising said compounds for the treatment in mammals ofdisorders responsive to selective GABA_(B) -receptor blocking,particularly cognitive and memory disorders, and also of depressions andanxieties.

One aspect relates advantageously to the method of treatment ofnootropic disorders in mammals, using an effective amount of a compoundof the invention, preferably in the form of above-cited pharmaceuticalcompositions.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration.

A unit dosage for a mammal of about 50 to 70 kg may contain betweenabout 10 and 500 mg of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 2 and 13 kPa.The structure of final products, intermediates and starting materials isconfirmed by analytical methods, e.g. microanalysis and spectroscopiccharacteristics (e.g. MS, IR, NMR). The compounds of formula I arehereinafter referred to as 3-amino-1-R¹ -R² -3-R³ -propyl(R)phosphinicacids.

EXAMPLE 1

To a solution of 1.0 g of ethyl3-amino-2-(p-chlorophenyl)propyl(diethoxymethyl)phosphinate in 5 ml ofmethanol are added 2.5 ml of a 2 normal sodium hydroxide solution andthe mixture is heated to a temperature of 80° for a period of 5 hours.After this time, the reaction is concentrated under reduced pressure,and the oily residue is passed down an Ion Exchange Resin (DOWEX®50W-X8H⁺) using de-ionised water as eluant. Ninhydrin-positive fractions arecombined and evaporated to give3-amino-2-(4-chlorophenyl)-propyl(diethoxymethyl)phosphinic acid, m.p.175-185° (dec.), ³¹ P-NMR : δ=+31.6 ppm (D₂ O).

EXAMPLE 2

0.5 g of ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate isdissolved in 5 ml of ethanol and this solution is added to a solution of0.14 g of sodium hydroxide in 2 ml of water. This mixture is then heatedto 60° for a period of 3 hours, cooled to room temperature and thesolvent evaporated under reduced pressure. The oily residue is passeddown an Ion Exchange Resin (DOWEX®50W-X8 H⁺) using de-ionised water aseluant. Ninhydrin-positive fractions are combined and evaporated to give3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinic acid, m.p. 214-215°(dec.), ³¹ P-NMR : δ=+30.9 ppm (D₂ O).

The starting material may be prepared as follows:

To a solution of 25.0 g of ethyl(trimethylsilyl)diethoxymethylphosphonite in 200 ml of drytetrahydrofuran is added 19.2 g of 2,3-epoxypropylphthalimide under anatmosphere of nitrogen. To this stirred mixture is added a catalyticamount of dry zinc chloride and the mixture is then refluxed for aperiod of 2 hours. After cooling, the solvent is evaporated underreduced pressure, the residue dissolved in 100 ml of chloroform, andstirred vigorously with 50 ml of water for a period of 0.5hours. Theorganic layer is separated, dried over magnesium sulfate and the solventis removed under reduced pressure. The residue is heated to 100° at 6 Paof pressure for a period of 1 hour to leave as an oily residue ethyl2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphinate, ³¹ P-NMR :δ=+42.0 and +41.6 ppm (CDCl₃).

To a solution of 1.0 g of ethyl2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphinate in 23 ml ofisopropanol is added 4 ml of water. To this mixture is added 0.47 g ofsodium borohydride and this is stirred for a period of 24 hours at roomtemperature. After this time 2.6 ml of glacial acetic acid are carefullyadded and the reaction heated to 80° for a period of 2 hours. After thistime, the reaction is cooled to room temperature, the solvent evaporatedunder reduced pressure and the residue passed down a silica column usinga mixture of one part ethyl acetate to one part ethanol as eluant. Ethyl3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is obtained ascolourless oil, ³¹ P=+45.8 and +45.2 ppm (CDCl₃).

EXAMPLE 3

A solution of 6.7 g of3-(benzyloxycarbonylamino)propyl(n-butyl)phosphinic acid in 125 ml of 36% hydrochloric acid is heated at reflux for 1.5 hour. The mixture isevaporated to an oil and the oil is co-evaporated with water (2×50 ml)to give a white solid. This solid is then dissolved in 50 ml of drymethanol, 1-3 ml of propylene oxide is added and the solution is stirredat room temperature. The precipitated product is collected by filtrationand dried to give 3-aminopropyl(n-butyl)phosphinic acid, m.p. 231-234°(dec.), ³¹ P-NMR : δ=+44.6 ppm (D₂ O).

The starting material may be prepared as follows:

A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of wateris cooled to 5° , and the pH adjusted to 9.5 with 2 molar sodiumhydroxide solution. To this mixture is added 6.8 g of benzylchloroformate whilst maintaining the pH and temperature. After theaddition is complete the mixture is stirred for 3 hours at pH 9.5 atroom temperature and left to stand overnight. The mixture is thenextracted with 100 ml of ether and the aqueous layer stirred at 5° withan equal volume of chloroform. The mixture is acidified to pH 2, thechloroform layer separated, dried over magnesium sulfate and the solventevaporated under reduced pressure. The oily product is triturated withether to give a white solid,3-(N-benzyloxycarbonylamino)propylphosphinic acid, m.p. 53-55°, ³¹ P-NMR: δ=+36.6 ppm (CDCl₃).

To a solution of 3.0 g of 3-(N-benzyloxycarbonylamino)propylphosphinicacid in 50 ml of dry tetrahydrofuran is added 2.3 g of triethylamine.This mixture is stirred under an atmosphere of nitrogen for a period of0.5 hours, and then 2.5 g of trimethylchlorosilane is added. Thissolution is stirred for a period of 1 hour during which time aprecipitate forms. After this time, 7.6 g of 1-bromobutane is added andthe reaction is refluxed for a period of 24 hours. The mixture is thenallowed to cool to room temperature, 50 ml of water is added and thewhole stirred for 1 hour. The mixture is extracted with 200 ml ofchloroform, the organic layer dried over magnesium sulfate and thesolvent evaporated under reduced pressure. The oily product istriturated with ether to give a white solid, being3-(N-benzyloxycarbonylamino)propyl(n-butyl)phosphinic acid, m.p.116-118°, ³¹ P=+58.6 ppm (CDCl₃).

EXAMPLE 4

A solution of 3.3 g of lithium hydroxide monohydrate in 40 ml of wateris added to a solution of 20 g of ethyl3-aminopropyl(diethoxymethyl)phosphinate in 75 ml of ethanol. Themixture is stirred and approximately 25 ml of further water is added toobtain a clear solution. The solution is stirred at room temperatureuntil the reaction is complete after approximately 48 hours. This can bemonitored by ³¹ P-NMR. Then the solution is evaporated to give a cloudyoil, to which are added 50 ml of ethanol. The insoluble inorganic solidis removed by filtration and the filtrate evaporated. The residual oilyproduct which contains a little solid is triturated with acetone and theresulting solid filtered off (³¹ P NMR: δ=33.98 ppm; D₂ O). The filtratefrom this is evaporated and again triturated with a little acetone toyield a second crop of product. Both crops are combined and dissolved inwater. The solution is concentrated and extracted with chloroform toremove traces of starting material, then treated with charcoal. Thesolution is filtered to remove charcoal and reduced to a small volume.This crude product is then subjected to ion exchange chromatography(DOWEX®50W-X8 H⁺ form) using de-ionised water as eluent. Fractions of150 ml are collected. Fraction 44 and following fractions contain the3-aminopropyl(diethoxymethyl)phosphinic acid, which is obtained in pureform after evaporation, m.p. 209-210° (dec.).

EXAMPLE 5

To a solution of 8.0 g of isopropyl 3-aminopropyl(t-butyl) phosphinatein 80 ml of chloroform are added 11.7 ml of trimethylsilylbromide. Thereaction mixture is stirred at 50° for 4 hours and then at roomtemperature overnight. Removal of chloroform and excess oftrimethylsilylbromide under reduced pressure gives an oil which is takenup in ethanol. Propylene oxide is added and the white solid is filteredoff and dried over phosphorous pentoxide to yield3-aminopropyl(t-butyl)phosphinic acid x 0.15 H₂ O, m.p. 253-255°.

The starting material is prepared as follows:

A mixture of 24.7 g of isopropanol and 17.2 g of triethylamine in 35 mlof diethylether is added drop by drop to 30 g oft-butyldichlorophosphine in 100 ml diethylether. The temperature is keptbetween 5 to 10°. The solid is filtered off and the filtrate evaporated.The crude oil is purified by distillation to yield t-butylphosphonousacid-isopropylester as an oil, b.p. 82°/2 kPa, n²⁰ _(D) =1.4222.

To 15.7 g of t-butylphosphonous acid-isopropylester in 6.3 ml ofacrylonitrile are added 21 ml of sodium isopropylate (0.25 molar). Afterthe exothermic reaction (the temperature rises to 100°) the suspensionis filtered, the filtrate evaporated and the residue distillated toyield isopropyl 2-cyanoethyl(t-butyl)phosphinate as an oil, b.p. 121°/8Pa, n²⁰ _(D) =1.4480.

A mixture of 11.0 g of isopropyl 2-cyanoethyl(t-butyl)phosphinate, 17.0g of ammonia and 1.7 g of Raney-Nickel in 110 ml of ethanol ishydrogenated during 5 hours. The catalyst is filtered off and thesolvent removed by evaporation. The crude oil is purified byKugelrohr-distillation to yield isopropyl3-aminopropyl(t-butyl)phosphinate as an oil, b.p. 155°/1 Pa, n²⁰D=1.4600.

EXAMPLE 6

7.0 g of isopropyl 3-aminopropyl(n-propyl)phosphinate and 40 ml of 20 %hydrochloric acid are stirred at reflux temperature overnight. Thereaction mixture is evaporated to dryness, taken up in methanol andtreated with propylene oxide. The white solid is filtered off and driedover phosphorous pentoxide to yield 3-aminopropyl(npropyl)phosphinicacid x 0.1 H₂ O as white crystals, m.p. 210-213°.

3-Aminopropyl(n-propyl)phosphinic acid can also be prepared from thesame starting material by silylation with trimethylsilylbromide andsubsequent treatment with propylene oxide in ethanol, m.p. 213-215°.

The starting materials isopropyl 3-aminopropyl(n-propyl)phosphinate,b.p. 155°/6 Pa, n²⁰ _(D) =1.4571; isopropyl2-cyanoethyl(n-propyl)phosphinate, b.p. 132°/40 Pa, n²⁰ _(D) =1.4470;and n-propylphosphonous acid-iso

propylester, b.p. 93°/2.8 kPa; n²⁰ _(D) =1.4241 are prepared in asimilar way as described in the preceding example starting fromn-propyldichlorophosphine.

EXAMPLE 7

A mixture of 7.73 g of isopropyl 3-aminopropyl(ethyl)-phosphinate and 40ml of 20% hydrochloric acid is refluxed with stirring for 14 hours. Theclear solution is evaporated to dryness and the residue isrecrystallized from methanol/propylenoxide to give3-aminopropyl(ethyl)phosphinic acid as a white solid, m.p. 233-239°;H-NMR (D₂ O): 0.4-1.8 (m, 9H, PCH₂ CH₂ and PCH₂ CH₂); 2.7 (t, 2H,NCH.sub.); 4.55 (s, 3H, OH, NH₂).

The starting materials are prepared as follows:

To a solution of 262 g of ethyldichlorophosphine in 1200 ml ofdiethylether is added with stirring and cooling with ice at 5-10° asolution of 370 ml of isopropanol and 280 ml of triethylamine in 400 mlof diethylether. The reaction is exothermic. After stirring for 12 hoursat 20° the white precipitate is filtered off and the filtrate isfractionally distilled. There is obtained ethylphosphonousacid-isopropylester as a colorless liquid, b.p. 80-85°/26 kPa. To 34 gof ethylphosphonous acid-isopropylester and 16.45 ml of acrylonitrile isadded with stirring 40 ml of isopropanol containing 0.25 mol of sodiumisopropylate. The reaction is exothermic. After 1 hour stirring at 20°the mixture is fractionated. There is obtained isopropyl2-cyanoethyl(ethyl)phosphinate as a colorless oil, b.p. 102-104°/10 Pa.

To 34.1 g of isopropyl 2-cyanoethyl(ethyl)phosphinate in 500 ml ofisopropanol are added 60 ml of liquid ammonia and 6.8 g of Raney-Nickel.The mixture is heated to 80° and treated with hydrogen at 100 bar. After11/2 hours hydrogen-uptake stops. The reaction mixture is filtered andthe filtrate distilled to give isopropyl 3-aminopropyl(ethyl)phosphinateas a colorless oil, b.p. 75°/13 Pa.

EXAMPLE 8

A mixture of 1.5 g of 3-aminopropyl(phenyl)phosphinic acid in 10 ml ofwater and 7.9 ml of 1N hydrochloric acid is treated with hydrogen at 25°in the presence of 0.2 g of Nishimura-catalyst (Rh/PtO₂). After 1.2hours hydrogen up-take stops. The reaction mixture is filtered and thefiltrate evaporated to dryness. The residue is recrystallized frommethanol/propylenoxide to give 1.2 g of3-aminopropyl(cyclohexyl)phosphinic acid x 0,4 mol hydrochloric acid asa white solid, m.p. 202-203°.

The starting materials are prepared as follows:

To a solution of 270 ml of phenyldichlorophosphine in 1000 ml ofdiethylether is added with stirring and cooling with ice a solution of280 ml of ethanol and 280 ml of triethylamine in 500 ml of diethylether.After stirring for 14 hours at 20° the precipitate is filtered off andthe filtrate is fractionally distilled. There is obtainedphenylphosphonous acid-ethylester as a colorless liquid, b.p. 83-85°/6Pa.

To 42.45 g of phenylphosphonous acid-ethylester and 16.45 ml ofacrylonitrile are added with stirring 5 ml of sodium ethylate (1 molar).The reaction is exothermic. After 1 hour stirring at 20° the mixture isfractionally distilled. There is obtained ethyl2-cyanoethyl(phenyl)phosphinate as a colorless oil, b.p. 134-136°/7 Pa.

To 22.72 g of ethyl 2-cyanoethyl(phenyl)phosphinate in 400 ml of ethanolare added 34 g of liquid ammonia and 4.5 g of Raney-Nickel. The mixtureis heated to 80° and treated with hydrogen at 100 bar. After 30 minuteshydrogen up-take stops. The reaction mixture is filtered and thefiltrate distilled to give ethyl 3-aminopropyl(phenyl)phosphinate as acolorless oil, b.p. 110°/13 Pa.

A mixture of 6.83 g of ethyl 3-aminopropyl(phenyl)phosphinate and 30 mlof 20 % hydrochloric acid is refluxed with stirring for 4 hours. Theclear solution is evaporated to dryness and the residue isrecrystallized from methanol/propylenoxide to give3-aminopropyl(phenyl)phosphinic acid as a white solid, m.p. 298-300° .

EXAMPLE 9

A mixture of 14.76 g (0.12 mol) of 3-aminopropylphosphonous acid and96.72 g (0.6 mol) of hexamethyldisilazane is refluxed under anatmosphere of argon with stirring for 16 hours to give a solution. Tothis solution are added at reflux 60 ml of diethyleneglycoldimethylether and the solution is refluxed for additional 2 hours.

The reaction is cooled to 120° and 38.75 g (0.3 mol) ofN-ethyl-diisopropyl-amine are added within 20 minutes followed byaddition of 54.06 g (0.3 mol) of isobutyl iodide over a period of 20minutes. The reaction mixture is heated with stirring for 22 hours.After cooling to 10° , the white precipitate is filtered off and thefiltrate is evaporated under reduced pressure. The clear solution iscooled, diluted with dichloromethane (300 ml) and extracted three timeswith 2N hydrochloric acid (3×100 ml). The combined hydrochloricacid-extracts are evaporated in vacuo to dryness, and re-evaporatedtwice with water (2×100 ml) to give a white solid, which is suspended in600 ml of acetone and stirred for 1 hour at 20°.3-Aminopropyl(isobutyl)phosphinic acid hydrochloride (25.3 g), m.p.149°=155°, is isolated by filtration.

After recrystallisation from n-propanol/acetone (200/100 ml) pure3-aminopropyl(isobutyl)phosphinic acid hydrochloride of m.p. 154-156°,is obtained. 15.4 g of 3-aminopropyl(isobutyl)phosphinic acidhydrochloride are dissolved in 75 ml of methanol and 300 ml ofpropylenoxide are added with stirring. After standing overnight at 4°, awhite solid precipitates.

The precipitate is collected by filtration and recrystallized fromn-propanol to give pure 3-aminopropyl(isobutyl)phosphinic acid, m.p.250°-253° (dec.).

EXAMPLE 10

In a manner analogous to that described in Example 9,3-aminopropyl(n-hexyl)phosphinic acid, m.p. 242°-246°, hydrochloride:m.p. 196-198°, is obtained with n-bromohexae at 130°, 22 hours.

EXAMPLE 11

In a manner analogous to that described in Example 9,3-aminopropyl(allyl)phosphinic acid, m.p. 230°-234° (dec.),hydrochloride: m.p. 140-142°, is obtained by reaction with allylbromideat 60°, 16 hours.

EXAMPLE 12

In a manner analogous to that described in Example9-aminopropyl(n-pentyl)phosphinic acid m.p. 232°-236°, hydrochloride:m.p. 192-194°, is obtained by reaction with n-bromopentane at 120°, 16hours.

EXAMPLE 13

In a manner analogous to that described in Example 9,3-aminopropyl(n-heptyl)phosphinic acid, m.p. 232 °-236° (dec),hydrochloride m.p. 190-192°, is obtained by reaction with n-bromoheptaneat 120°, 16 hours.

EXAMPLE 14

In a manner analogous to that described in Example 9,3-aminopropyl(but-3-enyl)phosphinic acid, m.p. 215°-220°, hydrochloride:m.p. 170-172°, is obtained by reaction with 4-bromo-1-butene at 95°, 16hours.

EXAMPLE 15

In a manner analogous to that described in Example 9,3-aminopropyl(n-decyl)phosphinic acid, m.p. 225°-230°, hydrochloridem.p. 185-190°, is obtained by reaction with n-bromodecane at 120°, 20hours.

EXAMPLE 16

In a manner analogous to that described in Example 9,3-aminopropyl(isopentyl)phosphinic acid, m.p. 238°-240° (dec.),hydrochloride: m.p. 159-161°, is obtained by reaction with1-bromo-3-methylbutane at 120°, 22 hours.

EXAMPLE 17

In a manner analogous to that described in Example 9,3-aminopropyl(cyclopropylmethyl)phosphinic acid x 0,16H₂ O. m.p.235°-238° (dec.), hydrochloride: m.p. 144-146°, is obtained by reactionwith bromomethyl-cyclopropane at 100°, for 22 hours.

EXAMPLE 18

In a manner analogous to that described in Example 9,(1-methyl-3-aminopropyl)(n-butyl)phosphinic acid x 0,2H₂ O, m.p.212°-215°, hydrochloride: m.p. 137-139°, is obtained by reaction of1-methyl-2-amino-propylphosphonous acid with n-butylbromide at 100°, 48hours.

EXAMPLE 19

In a manner analogous to that described in Example 9,3-aminopropyl(pent-3-ynyl)phosphinic acid x 0,2H₂ O, m.p. 220°-224°(dec.), hydrochloride: m.p. 174-176°, is obtained by reaction with5-iodopent-2-yne at 60°, 16 hours.

EXAMPLE 20

In a manner analogous to that described in Example 9,3-aminopropyl(but-3-ynyl)phosphinic acid, m.p. 214°-218°, hydrochloride:m.p. 148-150°, is obtained by reaction with 4-iodobut-1-yne at 90°, 16hours.

EXAMPLE 21

In a manner analogous to that described in Example 9,3-aminopropyl(2-ethoxyethyl)phosphinic acid x 0,14H₂ O m.p. 202°-208°,is obtained by reaction with (2-bromoethoxy)ethane at 100°, 16 hours.

EXAMPLE 22

In a manner analogous to that described in Example 9,3-aminopropyl(2-methylbutyl)-phosphinic acid x 0,1H₂ O, m.p. 248°-254°,is obtained by reaction with 2-methylbutyliodide at 100°, 16 hours.

2-Methylbutyliodide may be prepared in the following manner.

17.63 g (0.20 mol) of 2-methyl-butanol is added slowly during 20 minuteswith stirring to a mixture of 43.3 g (0.227 mol) oftoluene-p-sulphonylchloride in 20 ml of dry pyridine, keeping thetemperature below 25° by external cooling. After stirring for 2 hours at20°, the mixture is poured into ice-water and extracted with ether. Theether layer is washed subsequently with 2 N sulphic acid, water andsaturated sodium hydrogencarbonate solution. After drying over sodiumsulphate, filtration and evaporation in vacuo 2-methylbutyltoluene-p-sulphonate are obtained as a yellow oil.

45.99 g (0.189 mol) of 2-methylbutyl toluene-p-sulphonate are dissolvedin 290 ml of acetone, 34.7 g (0.23 mol) of sodium-iodide is added at 20°and the mixture is stirred for 2 hours under reflux. After cooling to 0°the separated sodium toluene-p-sulphonate is removed by filtration, andthe solvent is evaporated through a 15 cm Vigreux-column at atmosphericpressure.

The crude product is dissolved in ether and washed with 10% sodiumthiosulphate solution, dried over sodium sulphate and filtred off.Evaporation of the solvent through a 15 cm Vigreux column, followed byfractionational distillation gives 2-methylbutyliodide; b.p. 93°/200mbar.

EXAMPLE 23

In a manner analogous to that described in Example 9,3-aminopropyl-(3-ethoxypropyl)-phosphinic acid x 0,1H₂ O, m.p.210°-218°; hydrochloride: m.p. 161-165°, is obtained by reaction with2-ethoxypropyliodide at 130°, 16 hours.

3-Ethoxypropyliodide may be prepared in the following manner.

20.8 g (0.20 mol) of 2-ethoxypropanol are added slowly during 20 minuteswith stirring to a mixture of 43.3 g (0.227 mol) oftoluene-p-sulphonylchloride and 20 ml of dry pyridine. The temperatureof the reaction mixture is kept at 20° with external cooling. Afterstirring for 2 hours at 20°, the mixture is poured into ice-water andextracted with ether. The ether layer is washed with 2N sulphuric acid,with water and with saturated sodium hydrogencarbonate solution. Afterdrying over sodium sulphate, filtration and evaporation in vacuo,2-ethoxypropyl toluene-psulphonate is obtained as a yellow oil.

A solution of 51.5 g (0.199 mol) of 2-ethoxypropyl toluene-p-sulphonateand 36.5 g (0.243 mol) of sodium iodide in 250 ml of acetone is stirredunder reflux for 2 hours. After cooling to 10°, the separated sodiumtoluene-p-sulphonate is removed by filtration, and the solvent isevaporated through a 15 cm Vigreux-column at atmospheric pressure.

The crude product is dissolved in ether and washed with a 10% (b.w.)solution of sodium thiosulphate. Drying over sodium sulphate, filtrationand evaporation of the solvent through a 15 cm vigreux column, followedby fractional distillation yields 3-ethoxypropyliodide, b.p. 97°/40mbar.

EXAMPLE 24

In a manner analogous to that described in Example 9,3-aminopropyl(3-methoxypropyl)phosphinic acid x 0,25H₂ O; m.p.197°-203°, hydrochloride: m.p. 146-148°, is obtained by reaction with2-methoxypropyliodide at 115°, 40 hours.

EXAMPLE 25

In a manner analogous to that described in Example 9,3-aminopropyl(but-2-ynyl)phosphinic acid x 1,2H₂ O; m.p. 110°-115°,hydrochloride: m.p. 154-158°, is obtained by reaction with1-bromo-2-butyne at 90° for 16 hours.

EXAMPLE 26

In a manner analogous to that described in Example 9,3-aminopropyl[2-(2-ethoxyethoxy)ethyl]phosphinic acid x 0.16H₂ O m.p.215°-225°, is obtained by reaction with [2-(2-ethoxyethoxy)ethyl]iodide.

EXAMPLE 27

In a manner analogous to that described in Example 9,3-aminopropyl(4,4,4-trifluorobutyl)phosphinic acid, m.p. 237-241°(decomp.), hydrochloride: m.p. 144°-146°, is obtained by reaction with4,4,4-trifluorobutyliodide at 95°, 16 hours.

EXAMPLE 28

In a manner analogous to that described in Example 9,3-aminopropyl(2-methylthioethyl)phosphinic acid is obtained by reactionwith 1-chloro-2-methylthio-ethane at 100°, 16 hours.

EXAMPLE 29

In a manner analogous to that described in Example 9,3-aminopropyl(methylthiomethyl)phosphinic acid is obtained by reactionwith methylthiomethyl chloride at 75°, 16 hours.

EXAMPLE 30

In a manner analogous to that described in Example 9,3-aminopropyl(2-phenylethyl)phosphinic acid, m.p. 265°-270° is obtainedby reaction with 2-phenylethylbromide at 120°, 16 hours.

EXAMPLE 31

In a manner analogous to that described in Example 9,3-aminopropyl(2-methylallyl)phosphinic acid, m.p, 140°-143°, is obtainedby reaction with methallyl chloride at 63°, 24 hours.

EXAMPLE 32

A solution of 2.4 g of 3-benzyloxycarbonylaminopropyl(dodecyl)phosphinicacid in 50 ml of 36% hydrochloric acid is refluxed for 3 hours. Duringthis time, a white precipitate is formed. After cooling to roomtemperature the acid is removed by co-evaporation with 6×50 ml of wateron a rotary evaporator.

The crude product is then dissolved in 50 ml of ethanol and stirred with5 ml of propylene oxide. Filtration and drying gives3-aminopropyl(dodecyl)phosphinic acid as a white solid m.p. 175-7°. ³¹P-NMR =43.0 ppm (NaOD).

The starting material can be prepared as follows:

A solution of 1.30 g of dodecene in 6 ml of dry toluene is heated to 80°under an atmosphere of argon. To this solution a suspension of 2.0 g of3-benzyloxycarbonylaminopropylphosphonous acid in 30 ml of dry toluenecontaining 0.6 g of t-butylcyclohexylperdicarbonate is added within 15minutes. The reaction mixture is then stirred at 80° for 2 hours. Anadditional amount of 0.6 g of the radical initiator is added andstirring at 80° is continued for 2 hours. Then, the reaction mixture iscooled to room temperature and the solvent is removed by means of arotary evaporator. The residue is triturated with petroleum ether(60-80°), filtered and dried to give3-benzyloxycarbonylaminopropyl(dodecyl)phosphinic acid as a white solid,m.p. 115-6°; ³¹ P-NMR: δ=+58.7 ppm (CDCl₃).

EXAMPLE 33

To a solution of 5.7 g (0.0224 mol) of isopropyl3-aminopropyl(benzyl)phosphinate in 50 ml of chloroform 9.91 ml (0.0922mol) of trimethylsilylbromide are added raising the temperature to 44°.The reaction mixture is stirred at 50° for 4 hours and then at roomtemperature overnight. Removal of the chloroform and excesstrimethylsilylbromide under reduced pressure yields an oil which istaken up in isopropanol and 20 ml of propylene oxide. After stirring for10 minutes, a white solid precipitates. The solid is filtered off anddried over phosphorous pentoxide yielding3-aminopropyl(benzyl)phosphinic acid, m.p. 278-280°.

The starting material can be prepared from benzyl-dichloro-phosphine viabenzylphosphonous acid isopropylester, b.p. 113° (1 mbar), isopropyl2-cyanoethyl(benzyl)phosphinate, m.p. 69-72°, and isopropyl3-aminopropyl(benzyl)phosphinate, b.p. 113° (1 mbar).

EXAMPLE 34

A suspension of 1,23 g (10 mmol) of 3-aminopropylphosphonous acid in10.4 ml (50 mmol) of hexamethyldisilazane is heated to reflux underargon for 24 hours. 5 ml of diethylene glycol dimethyl ether are addedto the clear solution obtained and the mixture is heated for addtitional2 hours and then cooled to 0°. 8.5 ml (50 mmol) ofN-ethyl-N,N-diisopropyl-amine are added, followed by slow addition of3.8 ml (50 mmol) of propargyl bromide over a period of 40 minutes. Themixture is stirred for 1 hour at 0° and 4 hours at room temperature,filtered and evaporated under high vacuum. The residue is dissolved in10 ml of dichloromethane and extracted with 3×10 ml of lN hydrochloricacid solution. The water layer is evaporated under high vacuum and theresidue obtained dissolved in 4 ml of methanol at 0°. 20 ml of propyleneoxide are added during a period of 1 hour, after which time a crudeproduct precipitates. Chromatography (silicagel Merck 230-400 ASTM,methanol) followed by recrystallization (methanol/ether) yields3-aminopropyl(propargyl)-phosphinic acid, m.p. 172-173°.

EXAMPLE 35

To a solution of 0.90 g (4.0 mmol) of3-aminopropyl(diethoxymethyl)phosphinic acid in 10 ml of glacial aceticacid at 0° there are added 0.38 ml (4,4 mmol) of ethane-1,2-dithiol,followed by addition of 2 ml of concentrated hydrochloric acid over aperiod of 5 min. The mixture is allowed to warm to room temperature andis then stirred for 18 hours. After removal of acetic and hydrochloricacids under high vacuum, the residue is chromatographed (Opti-Up® C₁₂50%, water) and recrystallized from methanol to yield3-aminopropyl(1,3-dithiolan-2-yl)phosphinic acid, m.p. 272-274°.

EXAMPLE 36

To 590 mg (2.20 mmol) of lithium hydroxide monohydrate in 1.1 ml ofwater a solution of 2 mmol of ethyl3-aminobutyl(diethoxymethyl)phosphinate in 2.1 ml of ethanol, and then 1ml of water are added. The mixture is stirred 48 hours at roomtemperature and evaporated in vacuo. 3 ml of water are added to dissolvethe precipitate formed. Then 85 mg of 84% (b.w.) phosphoric acid areadded slowly and the suspension is stirred for 18 hours at roomtemperature. After filtration of the precipitate through celite,evaporation to dryness, chromatography (Opti-Up® C₁₂ 50%, H₂ O) andrecrystallisation from ethanol, 3-aminobutyl(diethoxymethyl)phosphinicacid, m.p. 225-228°, is obtained.

The starting material may be obtained as follows:

A mixture of 2.7 g of ethyl trimethylsilyldiethoxymethylphosphonite and0.7 g of methyl vinyl ketone is warmed to 50° for 1 hour under anatmosphere of nitrogen. Then 10 ml of water are added and the mixture isstirred for additional 30 minutes. The residue is extracted thrice with50 ml of chloroform, the organic phases are combined, dried overmagnesium sulphate, filtered and evaporated to dryness. The residue isthen distilled to yield ethyl 3-oxobutyl(diethoxymethyl)phosphinate,b.p. 130-5° (13.6 mbar).

A mixture of 1.0 g of ethyl 3-oxobutyl(diethoxymethyl)phosphinate 2.85 gof ammonium acetate and 0.16 g of sodium cyanoborohydride in 20 ml ofmethanol is stirred for 2.5 hours. After standing overnight, the pH isadjusted to pH 5,6 with 2N hydrochloric acid. The mixture is thenevaporated to dryness. 20 ml of water are added and the mixture iswashed 3 times with 20 ml of diethyl ether. The aqueous layer isadjusted to pH 12 with potassium hydroxide and extracted 4 times with 25ml of chloroform. The organic layers are combined, dried, filtered andevaporated to dryness yielding ethyl3-aminobutyl(diethoxymethyl)phosphinate, ³¹ P-NMR spectrum: δ=+46.0 ppm(CDCl₃).

EXAMPLE 37

In an analogous manner, by saponification with lithium hydroxide inaqueous ethanol3-amino-1-(p-chlorophenyl)-propyl(diethoxymethyl)phosphinic acid isobtained as a yellow oil; ¹ H-NMR (CDCl₃): δ 7.2-7.4 (m, 4), 4.1 (d, 1,J=6.5 Hz), 3.7 (m, 2), 3.6 (m, 2), 3.3 (t, 1, J=7.5 Hz), 3.1 (m, 2), 3.0(m, 4), 2.7 (m, 2), 2.2 (broad, 2), 1.2 (m, 6).

The starting material, ethyl3-amino-1-(p-chlorophenyl)propyl(diethoxymethyl)phosphinate, may beobtained as follows:

A mixture of 25.8 g of ethyl diethoxymethylphosphinate, 18.0 g of4-chlorcinnamoyl nitrile and 100 ml of ethanol is added dropwise at 0 to5° to a stirred solution of 1.2 g of sodium hydride (50% suspension inmineral oil) in 30 ml of ethanol. Then the ethanol is evaporated, theresidue is dissolved in 100 ml of chloroform and washed twice with 25 mlof water, the organic phase is dried over magnesium sulfate, filteredand evaporated to yield 20 g of ethyl1-(p-chlorophenyl)-2-cyano-ethyl(diethoxymethyl)phosphinate as an oil,³¹ P-NMR: δ+37.8 and +37.9 ppm (CDCl₃).

A solution of 20.0 g of ethyl1-(p-chlorophenyl)-2-cyano-ethyl(diethoxymethyl)phosphinate in 131 g ofa 8% (b.w.) ethanolic solution of ammonium is stirred with 8.5 ml ofRaney Nickel in 85 ml of ethanol, and hydrogenated until hydrogen uptakeceased. Filtration and evaporation then gives ethyl3-amino-1-(p-chlorophenyl)propyl(diethoxymethyl)phosphinate as an oil.

EXAMPLE 38

To a stirred solution of 0.05 g of lithium hydroxide monohydrate in 7.7ml of water, is added a solution of 4.37 g of ethyl3-aminopropyl(di-n-propyloxymethyl)phosphinate in 16.2 ml of ethanol. Aslight exothermic reaction ensues and the reaction mixture becomescloudy. A further 2 ml of water are added and the clear solution stirredat room temperature for 5 days. After this time the mixture isconcentrated in vacuo at 55° and the residue redissolved in water andextracted with 3×10 ml of dichloromethane. The aqueous layer is againevaporated to dryness and the residue dissolved in 20 ml of water andtreated with 0.51 ml of 85% phosphoric acid. After stirring overnight,the solid is removed by filtration. Evaporation of the filtrate andcrystallisation of the residue from ethanol/ether affords3-aminopropyl(di-n-propyloxymethyl)phosphinic acid, m.p. 223-225°, as awhite solid.

The starting material may be prepared as follows:

A mixture of 6.6 g of hypophosphorous acid (95% solution in water) and 6g of tri-n-propyl orthoformate is treated with 0.77 ml of trifluoraceticacid. The two-phase mixture is stirred at room temperature for 48-72hours until the reaction is complete. This can be monitored by ³¹ P-NMRor thin layer chromatography. The reaction mixture is diluted with 200ml of dichloromethane and washed twice with 150 ml of a saturatedaqueous solution of sodium bicarbonate. After drying the dichloromethanelayer over anhydrous magnesium sulphate and removal of the solvent invacuo, a colorless oil is obtained which after distillation affordsdi-n-propyloxymethylphosphonous acid n-propyl ester, b.p. 45°/2×10 mbar.

A solution of sodium ethoxide in absolute ethanol (0.48 g of sodiummetal in 15 ml of absolute ethanol) is cooled to 0° under nitrogen orargon. A solution of 2.72 g of acrylonitrile and 12.2 g ofdi-n-propyloxymethylphosphonous acid n-propylester in 50 ml of absoluteethanol is added at such a rate that the temperature does not exceed 5°.After the addition is completed, the solution is allowed to warm to roomtemperature and stirred overnight. After addition of 1.22 g of glacialacetic acid, the reaction mixture is concentrated in vacuo. The residueis partitioned between ethyl acetate and water and the organic phaseseparated. After drying over anhydrous magnesium sulphate the solvent isevaporated in vacuo to afford an oil. Chromatography on silica-gelyields ethyl 2-cyanoethyl(di-n-propyloxymethyl)phosphinate as acolourless oil.

A mixture of 4,35 g of ethyl2-cyanoethyl(di-n-propyloxymethyl)phosphinate, 10 g of ammonia and 2.3 gof Raney-Nickel in 170 ml of ethanol is hydrogenated for 10.5 hours. Thecatalyst is filtered off and the solvent is removed by evaporation. Thecrude oil is purified by distillation to yield ethyl3-aminopropyl(di-n-propyloxymethyl)phosphinate as a colourless oil.

EXAMPLE 39

In a manner analogous to that described in Example 38,3-aminopropyl(diisopropyloxymethyl)phosphinic acid, m.p. 175° m.p.(dec.) can be prepared.

The starting materials: Diisopropyloxymethylphosphonous acidisopropylester, b.p. 48°, 2×10⁴ mbar; ethyl2-cyanoethyl(diisopropyloxymethyl)phosphinate and ethyl3-aminopropyl(diisopropyloxymethyl)phosphinate are prepared as describedin Example 38 from hypophosphorous acid and triisopropyl orthoformiate.

EXAMPLE 40

In a manner analogous to that described in Example 38,3-aminopropyl(di-n-butyloxymethyl)phosphinic acid, m.p. 221-224°, can beprepared.

The starting materials: di-n-butyloxymethylphosphonous acidn-butylester, b.p. 75°, 2.0×15⁻⁴ mbar; ethyl2-cyanoethyl(di-n-butyloxymethyl)phosphinate and ethyl3-aminopropyl(di-n-butoxymethyl)phosphinate are prepared as described inExample 38 from hypophosphorous acid and tri-n-butyl orthoformiate.

EXAMPLE 41

To a stirred solution of 0.57 g of lithium hydroxide monohydrate in 10ml of water is added a solution of 2.0 g ofethyl-3-aminopropyl(tetrahydrofuran-2-yl)phosphinate in 20 ml ofethanol. A slight by exothermic reaction ensues and the reaction mixturebecomes turbid. A further 5 ml of water is added and the then clearsolution stirred for 3 days at room temperature. After this time, thereaction mixture is concentrated in vacuo at 55°, The residue isre-dissolved in water and washed with 3×10 ml of dichloromethane. Theaqueous layer is again evaporated to dryness and the residue dissolvedin 10 ml of water and treated with 0.65 ml of 85% phosphoric acid in 2ml of water. After stirring overnight, the solid is removed byfiltration. Evaporation of the filtrate and crystallisation of theresidue from methanol/ether affords3-aminopropyl(tetrahydrofuran-2-yl)phosphinic acid, m.p. 222-223°(dec.), as a white solid.

The starting material can be prepared either from diethoxymethyl- ordiethoxyethylphosphonous acid as follows:

A solution of 12.7 g of diethoxymethylphosphonous acid ethyl ester and6.95 g of 4-chlorobutanal in 10 ml of absolute ethanol is cooled to 0°under inert gas. Ethanolic sodium ethoxide (from 1.5 g of sodium metaland 20 ml of absolute ethanol) is added dropwise so that the temperaturedoes not rise above 5°. After the addition is completed, the reactionmixture is warmed to room temperature and stirred for 20 hours. Afterthis time a suspension results and the solvent is removed in vacuo. Theresidue is dissolved in dichloromethane/water and the organic layerseparated and washed with a further 20 ml of water. After drying withanhydrous magnesium sulphate and removal of the solvent in vacuoO-ethyl-P-Piethoxymethyltetrahydrofuran-2-yl-phosphinate, b.p.125°/1×10-2 mbar, is obtained.

A suspension of 5.32 g of 0-ethyl-P-diethoxymethyltetrahydrofuran-2-ylphosphinate in 50 ml of 6.0 M aqueous hydrochloric acid is heated to100° for 16 hours. After this time the solution is evaporated to drynessin vacuo and the residue co-evaporated in vacuo with 5×20 ml of waterfollowed by 5×20 ml of water followed by 5×10 ml of absolute ethanol.Drying the residue over phosphorous pentoxide in high vacuum at roomtemperature yields P-tetrahydrofuran-2-yl-phosphonous acid; ¹ H-NMR(CDCl₃): δ11.24 (1 H, s exchanges with D₂ O), 6.97 (1 H, d, J=557 Mz),4.07 (1 H, a). 3.90 (2 H, t, CH₂ O), 2.15 (2 H, m), 1.99 (2 H, m).

A solution of 2.6 g of P-tetrahydrofuran-2-yl-phosphonous acid in 20 mlof anhydrous dichloromethane is cooled to 5° under inert gas and treatedwith 2.03 g of triethylamine. A dichloromethane solution of 2.17 g ofethyl chloroformate is added dropwise whereupon an exothermic reactionand a gas evolution ensues. The suspension is warmed to room temperatureand stirred for 3 hours. The reaction mixture is then diluted withdichloromethane and washed with water. Drying of the organic phase withanhydrous magnesium sulphate and removal of the solvent in vacuo affordsP-tetrahydrofuran-2-yl phosphonous acid ethyl ester, b.p. 90°/8×10-2mbar.

A mixture of 0.68 g of acrylonitrile and 2.11 g of tetrahydrofuran-2-ylphosphonous acid ethyl ester in 5 ml of absolute ethanol is cooled to 0°under argon and treated, dropwise, with an ethanolic solution of sodiumethoxide (from 0.15 g of sodium metal and 15 ml of absolute ethanol) atsuch a rate so that the temperature does not exceed 5° (extremelyexothermic). After the addition is completed the reaction mixture isstirred at room temperature for 30 minutes and 0.4 g of glacial aceticacid are added. The solvent is removed in vacuo and the residuepartitioned between dichloromethane water. The organic layer is driedwith anhydrous magnesium sulphate and removed in vacuo to afford ethyl2-cyanoethyl(tetrahydrofuran-2-yl)-phosphinate; ¹ H-NMR (CDCl₃): δ4.15(3 H, m), 3.90 (2 H, m), 2.72 (2 H, m, CH₂ CN), 2.34-1.87 (6 H, m), 1.32(3 H, m, CH₃ ).

A solution of ethyl-2-cyanoethyl(tetrahydrofuran-2-yl)phosphinate inabsolute ethanol containing 10% by weight of ammonia is hydrogenatedover Raney-Nickel for 2.5 hours. The catalyst is removed by filtrationand the solvent removed in vacuo to affordethyl-3-aminopropyl(tetrahydrofuran-2-yl) phosphinate; ¹ H-NMR (CDCl₃):δ4.24 (4 H, m), 3.95 (1 H, m), 2.88 (2 H, sharpens on D₂ O addition: CH₂NH₂), 2.40-1.75 (6 H, m), 1.32 (3 H, t).

A solution of 2.10 g of 1,1-diethoxyethylphosphonous acid ethyl esterand 1.06 g of 4-chlorobutanal in 10 ml of absolute ethanol is cooled to0° under inert gas. Ethanolic sodium ethoxide (from 0.23 g of sodiummetal and 20 ml of absolute ethanol) is added dropwise so that thetemperature does not exceed 5°. After the addition is completed, thereaction mixture is warmed to room temperature and stirred for 20 hours.After this time a suspension results and the solvent is removed invacuo. The residue is dissolved in dichloromethane/water and the organiclayer separated and washed with a further 20 ml of water. After dryingof the organic phase with anhydrous magnesium sulphate and evaporationin vacuo ethyl 1,1-diethoxyethyl(tetrahydrofuran-2-yl)phosphinate isobtained as a clear oil, b.p. 110°/1×10⁻² mbar.

A solution of 1 g of ethyl1,1-diethoxyethyl(tetrahydrofuran-2-yl)phosphinate in 10 ml ofdichloromethane containing 1% (b.v.) of ethanol is treated with 0.71 gof trimethylsilylchloride. The faintly cloudy solution is stirredovernight at room temperature after which time thin layer chromatographyindicates complete reaction. Removal of the solvent in vacuo affords acolourless oil which after distillation yieldsP-tetrahydrofuran-2-yl-phosphonous acid ethyl ester, b.p. 90°/8×10⁻²mbar

Further elaboration of P-tetrahydrofuran-2-yl-phosphonous acid ethylester to ethyl 2-cyanoethyl(tetrahydrofuran-2-yl)phosphinate and ethyl3-aminopropyl(tetrahydrofuran-2-yl)phosphinate proceeds in a manneridentical to that described in example 41.

EXAMPLE 42

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 24hours. The resulting clear solution is cooled to room temperature and14.8 g of freshly distilled n-butyraldehyde are added. An exothermicreaction ensues, the reaction temperature, rising to approximately 60°C. The reaction mixture is stirred for 1 hour at a temperature between10° and 60°. After cooling to room temperature, the volatile materialsare removed in vacuo to yield a colourless oil. This oil is dissolved inwater and stirred at room temperature for 1 hour and the aqueous layeris evaporated to dryness at 55°. A semi-solid residue is obtained whichis dissolved in 50 ml of 2.0 M aqueous hydrochloric acid and washed withdichloromethane, (3×100 ml), and ether (1×100 ml). After removal of thewater the white solid is co-evaporated with water (10×50 ml), and thenwith 10×50 ml of absolute ethanol. Crystallisation of the residue formethanol yields 3-aminopropyl(1-hydroxybutyl)phosphinic acidhydrochloride, m.p. 154-160°. Treatment of the hydrochloride withpropylene oxide/ethanol or passage through a DOWEX® 50 W x 8 (14-40mesh) ion-exchange column gives 3-aminopropyl(1-hydroxybutyl)phosphinicacid, m.p. 187-188°, as a white solid.

EXAMPLE 43

In a manner analogous to that described in Example 42,3-aminopropyl(1-hydroxyisobutyl)phosphinic acid hydrochloride, m.p. 105°(dec.) and 3-aminopropyl(1-hydroxyisobutyl)phosphinic acid, m.p.122-123° are obtained by reaction with isobutyraldehyde at 40-60° for 1hour.

EXAMPLE 44

In a manner analogous to that described in Example 42,3-aminopropyl(1-hydroxyethyl)phosphinic acid hydrochloride, m.p.153-154° and 3-aminopropyl(1-hydroxyethyl)phosphinic acid, m.p. 255-256°may be obtained by reaction with acetaldehyde at 0-15° for 1 hour.

EXAMPLE 45

In a manner analogous to that described in Example 42,3-aminopropyl(1-hydroxybenzyl)phosphinic acid hydrochloride, m.p.173-174° and 3-aminopropyl(1-hydroxybenzyl)phosphinic acid, m.p.139-140° are obtained by reaction with freshly distilled benzaldehyde at40-60° for 1 hour.

EXAMPLE 46

In a manner analogous to that described in Example 42,3-aminopropyl(1-hydroxy-4,4,4-trifluoro-butyl)phosphinic acidhydrochloride, m.p. 139,5-140° and3-aminopropyl(1-hydroxy-4,4,4-trifluorobutyl)phosphinic acid, m.p.226-227° are obtained by reaction with 4,4,4-trifluorobutanal at 20° for1 hour.

EXAMPLE 47

In a manner analogous to that described in Example 42,3-aminopropyl[1-hydroxy-(Z)-2-fluoro-but-2-enyl]phosphinic acidhydrochloride, m.p. 110-112° and3-aminopropyl(1-hydroxy-2-fluoro-(Z)but-2-enyl)phosphinic acid, m.p.121-122° are obtained by reaction with (Z)-2-fluorocrotonaldehyde at 0°(very exothermic) for 1 hour.

EXAMPLE 48

In a manner analogous to that described in Example 42,3-aminopropyl(l-hydroxy-l-cyclopropylmethyl)phosphinic acidhydrochloride, m.p. 135-136° and3-aminopropyl(l-hydroxy-l-cyclopropylmethyl)phosphinic acid, glass: δ(¹H-NMR, D₂ O); 2.90 (3 H, d and t, CHOH, CH₂ NH₂), 1.77 (4 H. m), 0.89 (2H, m, CH). 0.49 (2 H, m, CH₂). 0.22 (2 H, m, CH₂) are obtained byreaction with 1-formyl cyclopropane at 20° for 1 hour.

EXAMPLE 49

In a manner analogous to that described in Example 42,3-aminopropyl[1-hydroxy-1-(2-methylthiocyclopropyl)methyl]phosphinicacid hydrochloride, m.p. 100° (dec.) and3-aminopropyl[1-hydroxy-1-(2-methylthiocyclopropyl)methyl]phosphinicacid, m.p. 105-106° may be obtained by reaction with1-formyl-1-methylthiocyclopropane at 40°-60° for 1 hour.

EXAMPLE 50

In a manner analogous to that described in Example 42,3-aminopropyl(1-hydroxy-1-cyclobutylmethyl)phosphinic acidhydrochloride, m.p. 167-168° and3-aminopropyl(1-hydroxy-1-cyclobutylmethyl)phosphinic acid, m.p.225-226° are obtained by reaction with 1-formylcyclobutane at 40-60° for1 hour.

EXAMPLE 51

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 24 hoursafter which a clear solution results. The excess hexamethyldisilazane isremoved by distillation at atmospheric pressure under a slight positivepressure of inert gas to afford a colourless oil. The oil is cooled tocirca 40° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of1,2-epoxybutane. An exothermic reaction occurs and the epoxybutanerefluxes. Reflux is continued for 6 hours after which time thin layerchromatography indicates the reaction to be complete. The reactionmixture is filtered and the filtrate evaporated to dryness in vacuo at40°. The residue is dissolved in water and stirred at room temperaturefor 1 hour and the water removed in vacuo to give an oily solid. This isdissolved in some 2.0 M aqueous hydrochloric acid and washed withdichloromethane and ether. Removal of the water at 40° in vacuo affordsa brown solid which is purified by ion-exchance chormatography on DOWEX®50 W x 8 (14-40 mesh) to give 3-aminopropyl(-2-hydroxybutyl)phosphinicacid, m.p. 184-185°, as a white solid.

EXAMPLE 52

In a manner analogous to that described in Example 51,3-aminopropyl[2-(R)-hydroxy-3-methylbutyl]phosphinic acid, m.p. 187-189°is obtained by reaction with (R)-(-)-1,2-epoxy-3-methylbutane at 70°.

EXAMPLE 53

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 24hours. The resulting clear solution is cooled to 15° and 2.0 ml ofcyclobutanone are added. An exothermic reaction ensues. The reactionmixture is stirred until the temperature drops to room temperature(approximately 1 hour). Water is added and the volatile materials areremoved in vacuo to yield a semi-solid. This is dissolved in 2.0 Maqueous hydrochloride acid and washed with 2×100 ml of dichloromethane.The aqueous layer is evaporated in vacuo to afford a solid which ispassed through a DOWEX® 50 W x 8 (14-40 mesh) ion-exchange column togive 3-aminopropyl(1-hydroxycyclobutyl)phosphinic acid, m.p. 174-175°(dec).

EXAMPLE 54

A mixture of 3.0 g of 3-aminopropyl(benzyl)phosphinic acid hydrochlorideand 0.6 g of Nishimura catalyst in 30 ml of methanol is hydrogenatedduring 4 hours. The catalyst is filtered off and the solvent removed byevaporation. The residue is dissolved in 20 ml of methanol and 10 ml ofpropyleneoxide are added to the solution. Stirring for 3 hours affords awhite solid which is filtered off and dried over phosphorous pentoxideto yield 3-aminopropyl(cyclohexylmethyl)phosphinic acid, m.p. 230°(dec.).

EXAMPLE 55

A solution of 1 g of 3-aminopropyl(but-3-enyl)phosphinic acid in 25 mlof water is treated with 0.1 g of 5% palladium on charcoal andhydrogenated at room temperature until hydrogen uptake ceases. Thecatalyst is removed by filtration of the reaction mixture through celiteand the filtrate evaporated to dryness, to afford3-aminopropyl(butyl)phosphinic acid, m.p. 231-234° (dec.) ³¹ --NMR (D₂O): δ+44.6 ppm.

EXAMPLE 56

A suspension of 25.7 g of 3-(N-benzyloxycarbonylaminopropyl)phosphonousacid in 150 ml of anhydrous dichloromethane is cooled to 5° under aninert gas and 11.1 g of triethylamine is added. A slight exothermresults and all the solid dissolves. The solution is re-cooeed to 0° anda solution of 11.94 g of ethyl chloroformate in 100 ml of anhydrousdichloromethane is added dropwise over 15-30 minutes, maintaining thetemperature at 10°. The reaction is exothermic and gas evolutiontogether with the formation of a white precipitate is observed. Thewhite suspension is stirred for 1 hour at room temperature, diluted with500 ml of dichloromethane and washed with 2×200 ml of water. Afterdrying the organic phase with anhydrous magnesium sulfate andevaporation of the solvent in vacuo3-(N-benzyloxycarbonylaminopropyl)phosphonous acid ethyl ester isobtained as a colourless viscous oil; ¹ H-NMR: δ (CDCl₃); 7.35 (5 H, m,Ph), 7.13 (1 H, d, J=530 Hz, P-h), 5.08 (2 H, m, CH₂ Ph), 4.13 (2 H, m,P-OCH₂), 3.27 (2 H, brd, sharpens on D₂ O addition, CH₂, NH₂), 1.82 (4H, m, 2 x CH₂), 1.35 (3 H, t, CH₃)

A solution of 2.85 g of 3-(N-benzyloxycarbonylaminopropyl)phosphonousacid ethyl ester in 25 ml of anhydrous tetrahydrofuran is cooled to 0°under an inert gas and 2.22 g of triethylamine added followed bydropwise addition of a solution of 2.39 g of trimethylsilylchloride in25 ml of anhydrous tetrahydrofuran over 15 minutes. A slight exothermreaction occurs and a white precipitate is observed. The suspension isstirred at room temperature for 20 hours and filtered under inert gas.The solid is washed with a further 50 ml of anhydrous tetrahydrofuranunder inert gas and the combined organic filtrate evaporated to drynessin vacuo to afford a slightly cloudy colourless oil. This oil is treatedwith 10-15 ml of freshly distilled n-butyraldehyde maintaining an inertatmosphere. An exothermic reaction ensues, the temperature rising circa35°. The mixture is allowed to cool to room temperature, is diluted with100 ml of dichloromethane and washed with water, 0.1 ml of aqueoushydrochloride acid followed by water. Drying of the solvent and removalof the dichloromethane in vacuo yields ethyl3-(N-benzyloxycarbonylaminopropyl) (1-hydroxybutyl)phosphinate as amixture of diastereoisomers; ¹ H-NMR: δ(CDCl₃); 7.35 (5 H, m), 5.10 (1H, n), 4.25-3.98 (1 H, m, CHOH), 3.28 (2 H, t, CH₂ NH₂), 1.97-1.44 (4 H,m), 1.40-1.21 (4 H, m), 0.95 (3 H, t, CH₃)

A solution of 0.714 g of ethyl3-(N-benzyloxycarbonylaminopropyl)(1-hydroxybutyl)phosphinate in 10 mlof anhydrous dichloromethane at room temperature is treated with 0.712 gof N,N'-thiocarbonyl-diimidazole. The red solution is stirred for 20hours at room temperature, diluted with dichloromethane and washed withcold 1.Om aqueous hydorchloric acid (2×30 ml), water and saturatedaqueous sodium bicarbonate solution. The organic layer is dried and thesolvent removed in vacuo to afford ethyl3-(N-benzyloxycarbonylaminopropyl)-[1-(0thiocarbonylimidaz-1-oyloxy)butyl]phosphinateas a pale yellow oil: ¹ H-NMR: δ(CDCl₃); 8.46 (1 H, d, t), 7.47 (1 H. d.t), 7.35 (5 H, m, Ph), 7.07 (1 H, m), 6.12 (1 H, m, CHO), 5.10 (2 H, CH₂Ph), 4.25-3.98 (2 H, m, CH₂ OP), 3.25 (2 H, t, CH₂ NH₂), 1.97-1.44 (2 H,m, 2 x CH₂), 1.42-1.20 (4 H, m), 0.96 (3 H, t, CH₃)

A solution of ethyl3-(N-benzyloxycarbonylaminopropyl)-[1-(0-thiocarbonylimidaz-1-oyloxy)butyl]phosphinatein 10 ml of anhydrous degassed benzene is treated with 0.291 g oftri-n-butyltin hydride. The clear solution is brought to reflux and 0.08g of azobisisobutyronitrile added. Reflux is continued for 1 hour afterwhich time thin layer chromatography indicates the reaction to becomplete. The reaction is cooled to room temperature and the volatilematerial removed in vacuo to afford a pale yellow oil. The oil ispartitioned between acetonitrile methane and the acetonitrile layerseparated and washed with a further 2×20 ml hexane. Evaporation of theacetonitrile in vacuo and chromatography of the residual oil on silicagel affords ethyl 3-(N-benzyloxycarbonylaminopropyl)(n-butyl)phosphinateas an oil; saponification of this oil with lithium hydroxide followed byacidification with phosphoric acid affords3-(N-benzyloxycarbonylamino)propyl(n-butyl)phosphinic acid m.p. 116-118°described in example 3 yielding 3-aminopropyl(n-butyl)phosphinic acid,m.p. 231-234° (dec.).

EXAMPLE 57

A mixture of 2.0 g ethyl 3-aminopropyl(1-hydroxybutyl)-phosphinate and20.0 ml 2 M aqueous hydrochloric acid is refluxed for 2 hours and thenevaporated to dryness. The residual oil is dissolved in 10 ml of water,and re-evaporated. The residue is dissolved in 20 ml of ethanol andtreated with propylene oxide and to give 1.5 g of3-aminopropyl(1-hydroxybutyl)phosphinic acid, m.p. 188 °.

The starting material is prepared as follows:

A mixture of 24.5 g ethyl-(1,1-diethoxyethyl)phosphinate and 40 g ofhexamethyldisilazane are heated at 148° under a inert gas for 3 hours.The reaction mixture is cooled to room temperature and 6 g ofacrylonitrile a added. The mixture is stirred for 2 hours. The reactionmixture is evaporated, dissolved in aqueous methanol and re-evaporatedto give 25,7 g of ethyl 2-cyanoethyl(1,1-diethoxyethyl)phosphinate (³¹P-HMR:δ=N 44 ppm).

This oil is treated with 25.7 g of trimethylsilyl chloride in 150 ml ofcommercial grade chloroform (containing 1 to 5% b.w. of ethanol) t roomtemperature for 6 hours under argon. The reaction mixture is stripped,the oil is dissolved in methanol and re-evaporated to give ethyl2-cyanoethylphosphinate.

A mixture of 2.5 g of ethyl 2-cyanoethylphosphinate of 4.96 g ofhexamethyl disilazane is treated to 140° for 1 hour. The mixture iscooled to 50° and under 2,45 g of n-butyraldehyde are added. After 15minutes to mixture is stripped to an oil which is co-evaporated with 10ml of aqueous ethanol to give 3.7 g ethyl2-cyanoethyl(1-hydroxybutyl)phosphinate. Tis oil is dissolved in 50 mlof ethanol containing 0.58 g of ammania and 0.5 g of Raney Nickel andhydrogenated for 10 hours. The catalyst is filtered off and the solventis removed by evaporation to give 2.0 g of ethyl3-aminopropyl(1-hydroxybutyl-n-butyl)phosphinate

EXAMPLE 58

A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 20hours. After this time a clear solution results and the reaction mixtureis cooled to room temperature under inert gas and 50 ml of anhydrousacetone is added and an exothermic reaction results. The reactionmixture is allowed to cool to room temperature and the volatilecomponents removed in vacuo to afford a clear oil. This oil is dissolvedin 50 ml of a 2.0 M hydrochloric acid solution in water and washed with2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer isevaporated to dryness to give a semi-solid residue which isco-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml)yielding 3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloridem.p. 159-161° as a white solid. This is suspended in absolute ethanoland treated with propylene oxide. Filtration and drying of the solidaffords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p.243-244°.

EXAMPLE 59

In a manner analogous to that described (above) in Example 583-Aminopropyl-(1,2-dihydroxyprop-2-yl)phosphinic acid hydrochloride,m.p. 175-179° and 3-aminopropyl-(1,2-dihydroprop-2-yl)phosphinic acid,m.p. 209-210° (dec.) may be obtained by reaction with1-0-tertbutyldimethylsilyloxymethyl propan-2-one at 70° for 20 hours.

The starting material may be obtained as follows:

To a solution of 6.8 g of imidazole in 20 ml of anhydrousdimethylformamide is added 7.5 g of tert-butyldimethylsilyl chloride inthe same solvent at 10° under inert gas. The clear solution is stirredfor 15 minutes at 10° before addition of 20 ml of an anhydrousdimethylformamide solution of 3.7 g of hydroxy acetone. A slightexothermic reaction ensues and the reaction mixture is warmed to roomtemperature and stirred for 16 hours. Subsequently the reaction mixtureis diluted with ether and washed with water. After drying the organicphase with anhydrous magnesiumsulphate and removal of the ether in vacuothe clear oil is distilled to afford1-0-tert-butyldimethylsilyloxymethyl propan-2-one; b.p. 84-85°/18 mm Hg.

EXAMPLE 60

In an analogous fashion to that described in Example 51,3-amino-2-hydroxy-propyl(n-propyl)phosphinic acid and its hydrochloridecan be prepared by reaction of n-propylphosphonous acid ethyl ester withepoxypropylphthalimide.

EXAMPLE 61

In a manner analogous to that described in Example 9,3-amino-2-(p-chlorophenyl)-propyl(n-propyl)phosphinic acid and itshydrochloride can be prepared by reaction of n-propylphosphonous acidethyl ester with 1-phthalimido-2-(p-chlorophenyl)-3-bromo-propane.

EXAMPLE 62

In a manner analogous to that described in Example 42,3-amino-1-hydroxy-propyl(n-propyl)phosphinic acid and its hydrochloridecan be prepared by reaction of 3-(benzyloxycarbonylamino)propanal withn-propyl-phosphonousacid ethyl ester.

EXAMPLE 63

In a manner analogous to that described in Example 32,3-aminopropyl(4-hydroxybutyl)phosphinic acid and its hydrochloride canbe obtained from the reaction of 3-aminopropylphosphonous acid and4-hydroxybut-1-ene. Also, by the same method,3-aminopropyl(3-hydroxybutyl)phosphinic acid and its hydrochloride canbe obtained by reaction of 3-aminopropylphosphonous acid and3-hydroxybut-1-ene.

EXAMPLE 64

In a manner analogous to that described in Example 9,3-aminopropyl[2-(S)-methylbutyl]phosphinic acid, m.p. 252-255° (dec.)[α]²⁰ ₃₆₅ nm=+20.5°; [α]²⁰ ₄₃₆ nm=+13.8°; [α]²⁰ ₅₄₆ =+8°; ]α]²⁰ ₅₇₈=+6.6° and [α]²⁰ ₅₈₉ =6.1° (c=0.95 in water) is obtained by reactionwith (S)-(+) -2-methylbutyliodide at 120°, 16 hours.

EXAMPLE 65

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert atmosphere for24 hours after which a clear solution results. The excesshexamethyldisilazane is removed by distillation at atmospheric pressureunder a slight positive pressure of inert gas to afford a colourlessoil. The oil is cooled to circa 66° and treated with 0.64 g of anhydrouszinc iodide and 4.62 g of N-(2,3-epoxypropyl)phthalimide. An exothermicreaction occurs. The reaction mixture is refluxed for 6 hours afterwhich time thin layer chromatography indicates the reaction to becomplete. The reaction mixture is filtered and the filtrate evaporatedto dryness in vacuo at 40°. The residue is dissolved in water andstirred at room temperature for 1 hour and the water removed in vacuo togive an oily solid. This is dissolved in 25 ml of 2.0 M aqueoushydrochloric acid and washed with dichlormethane and ether. Removal ofthe water at 40° in vacuo affords a brown solid which is purified byion-exchance chromatography on DOWEX® 50 W x 8 (14-40 mesh) to give3-aminopropyl(2-hydroxy3-phthalimido-propyl)phosphinic acid, m.p.268°-71°, as a white solid.

This can be converted into3-aminopropyl(3-amino-2-hydroxy-propyl)phosphinic acid by methods knownper se.

EXAMPLE 66

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 24hours. The resulting clear solution is cooled to room temperature and14.4 g of freshly distilled methyl vinyl ketone are added. An exothermicreaction ensues, the reaction temperature rising to approximately 60° C.The reaction mixture is stirred for 1 hour at a temperature between 50°and 60°. After cooling to room temperature, the volatile materials areremoved in vacuo to yield a colourless oil. This oil is dissolved inwater and stirred at room temperature for 1 hour and the aqueous layeris evaporated to dryness at 55°. A semi-solid residue is obtained whichis dissolved in 50 ml of 2.0 M aqueous hydrochloric acid and washed withdichloromethane, (3×100 ml), and ether (1×100 ml). After removal of thewater, the white solid is co-evaporated with water (10×50 ml) and thenwith absolute ethanol (10× 50 ml). Crystallisation of the residue formethanol yields 3-aminopropyl(3-oxobutyl)phosphinic acid hydrochloride.Treatment of the hydrochloride with propylene oxide/ethanol or passagethrough a DOWEX® 50 W x 8 (14-40 mesh) ion-exchange column gives3-aminopropyl(3-oxobutyl)phosphinic acid, m.p. 163-5° (decomp.), as awhite solid.

EXAMPLE 67

A suspension of 1.3 g of ethyl3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate in 10ml of concentrated aqueous hydrochloric acid is heated to reflux for 20hours. The clear solution is cooled to room temperature and washed with1×50 ml of dichloromethane and 1×50 ml of ether. Evaporation of theaqueous layer affords a solid which is co-evaporated with 5×50 ml ofwater and 5×50 ml of absolute ethanol. Drying of the solid andcrystallisation from ethanol affords3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p.147-150°. Dissolution of the hydrochloride salt in ethanol and treatmentwith propylene oxide affords, after filtration and drying,3-amino-1-hydroxy-propyl(n-butyl)phosphinic acid, m.p. 123-125°.

The starting materials may be prepared as follows.

A mixture of 1.50 g of ethyl (n-butyl)phosphinate, 1.01 g triethylamineand 2.07 g 3-(N-benzyloxycarbonylamino)propionaldehyde is heated to 100°C. for 4 hours. After this time the mixture is cooled to 20° and thevolatile components are removed in high vacuum. Chromatography of theresidue on silica gel affords ethyl3-(N-benzyloxycarbonylamino)-1-hydroxy-propyl(n-butyl)phosphinate as aviscous oil.

EXAMPLE 68

A solution of 6.4 g of ethyl3-phthalimido-2-trimethylsilyloxy-propyl(ethyl)phosphinate in 100 ml ofconcentrated aqueous hydrochloric acid is heated to reflux for 20 hours.After this time the suspension is cooled to room temperature andfiltered. The filtrate is evaporated to dryness, the resultingsemi-solid is co-evaporated with water (5×50 ml) and absolute ethanol(5×100 ml) and the white solid is dried in high vacuum overnight.Crystallisation from absolute ethanol/acetone affords3-amino-2-hydroxy-propyl(ethyl)phosphinic acid hydrochloride, m.p.114-115°.

The starting material may be obtained as follows:

A solution of 21.0 g of ethyl 1,1-diethoxyethylphosphinate in 50 ml ofanhydrous tetrahydrofuran is added dropwise to a suspension of 4.36 g ofsodium hydride (55% dispersion in oil) in 150 ml of anhydroustetrahydrofuran under an inert atmosphere maintaining the temperature at15° C. After addition is complete the resulting suspension is stirredfor 1 hour at 20° C. before re-cooling to 15° and addition of 86 g ofethyl bromide in 50 ml anhydrous tetrahydrofuran.

The suspension is stirred for 16 hours at 20° C. and water (50 ml) iscarefully added. After concentration in vacuo, the residue is dissolvedin water and extracted with dichloromethane. The organic layer isseparated and dried over anhydrous magnesium sulphate. Removal of thesolvent in vacuo affords ethyl 1,1-diethoxyethyl(ethyl)phosphinate as a1 colourless oil; b.p. 80° at 4×10⁻¹⁴ 2 mbar.

A suspension of 19.14 g of ethyl 1,1-diethoxyethyl(ethyl)phosphinate in100 ml of 4.0 M aqueous hydrochloric acid is heated to reflux for 20hours. After cooling to 20° the solution is washed with dichloromethanefollowed by ether. Evaporation of the aqueous layer and coevaporation ofthe oily residue with 5×100 ml of water and 5×100 ml absolute alcoholaffords ethyl phosphonous acid.

A solution of 7.63 g of ethyl phosphonous acid in 150 ml of anhydrousdichloromethane is cooled to 0° under an inert atmosphere andtriethylamine added dropwise. To the resulting cloudy solution areadded, at 0°, 8.81 g of ethyl chloroformiate in 50 ml of anhydrousdichloromethane. The reaction becomes exothermic and vigorous gasevolution occurs. After warming to room temperature, the mixture isdiluted with 100 ml of dichloromethane and washed with 2×100 ml ofwater. Drying and removal of the solvent in vacuo affords ethylethylphosphinate as a colourless oil.

A mixture of 4.55 g of anhydrous triethylamine and 5.0 g of ethylethylphosphinate in 100 ml of anhydrous tetrahydrofuran under an inertatmosphere is treated with 4.89 g of chlorotrimethylsilane. Theresulting suspension is stirred for 20 hours at room temperature and thesolid removed by filtration. Concentration in vacuo affords a cloudy,colourless oil which is treated with 5.10 g of anhydrousN-(2,3-epoxypropyl)phthalimide and 1.0 g of anhydrous zinc chloride. Themixture is heated to 66° C. under an inert atmosphere for 3 hours,cooled to 20° and diluted with dichloromethane. The organic solution iswashed with 100 ml of a 10% aqueous sodium bicarbonate solution anddried over anhydrous magnesium sulphate. Removal of the solvents andchromatography on silica gel affords ethyl3-phthalimido-2-trimethylsilyloxy-propyl(ethyl)phosphinate as a viscousoil.

EXAMPLE 69

3-Aminopropyl(2-methoxyethyl)phosphinic acid x 0.13 H₂ O, m.p. 208-212°(hydrochloride: m.p. 114-115°) is obtained from 3-aminopropylphosphonousacid, hexamethyldisilazane, N-ethyl-N,N-diisopropylamine and2-chloroethyl methyl ether at 120° for 48 hours.

EXAMPLE 70

3-Aminopropyl(2-ethoxymethyl)phosphinic acid x 0.26 H₂ O, m.p. 220°-225°(dec hydrochloride: oil) is obtained from 3-aminopropylphosphonous acid,hexamethyldisilazane, N-ethyl-N,N-diisopropyl-amine andchloromethyl-ethylether at 25° for 120 hours.

EXAMPLE 71

A mixture of 1.4 g (5.8 mMol) of ethyl3-aminopropyl(1,1difluorobutyl)phosphinate and 15 ml of 12 Mhydrochloric acid is stirred for 8 hours at 80° C. The reaction mixtureis evaporated to dryness and the residue is recrystallized fromethanol/ether giving 3-aminopropyl(1,1-difluorobutyl)phosphinic acidhydrochloride, m.p. 149-151° C.

The starting material may be obtained as follows:

To a suspension of 15.8 g of sodium hydride (dispersion in oil) in 500ml of tetrahydrofuran are added dropwise 67 g (300 mMol) of ethyl1,1-diethoxyethylphosphinate at such a rate so that the temperature,exceed 25° C. This mixture is stirred for one hour at room temperature,then cooled to -10° C. and 77.8 g (900 mMol) of chlorodifluoromethaneare introduced. Stirring is continued for another 2 hours at roomtemperature, then 100 ml of ice-cold water are added. The mixture isextracted three times with dichloromethane and the combined extractsdried over magnesium sulphate. Removal of the solvent in vacuo givesethyl 1,1-diethoxyethyl(difluoromethyl)phosphinate as a viscous oil,Rf=0.44 (CH₂ Cl₂ /CH₃ COOH, 9+1).

To a solution of 15.6 g (60 mMol) of ethyl1,1-diethoxyethyl(difluoromethyl)phosphinate in 150 ml of drytetrahydrofuran is slowly added at -65° C. with stirring under argon48.8 ml (78 mMol) of n-butyllithium (1.6 moles in hexane). This mixtureis stirred for additional 15 minutes at this temperature. Still at -65°C., 71 ml (78 mMol) of n-propylbromide are added dropwise and then thereaction mixture is allowed to warm to 0° C. and stirring is continuedfor 1 hour.

Water is added and the mixture is extracted three times with ether. Theorganic layer is washed once with water dried over magnesium sulphateand evaporated giving a yellow oil. This is chromatographed on 600 g ofsilica gel eluting with ether. The product-containing fractions arecollected and the solvent is evaporated to leave pure ethyl1,1-diethoxyethyl(1,1-difluorobutyl)phosphinate, Rf=0.5 (CH₂ Cl₂ /CH₃COOH, 9+1).

To 8.2 g (27.1 mMol) of ethyl1,1-diethoxyethyl(1,1-difluorobutyl)phosphinate in 81 ml of drytetrahydrofuran are added, with stirring at room temperature, 9 ml ofethanol and 5.1 ml (40.7 mMol) of trimethylchlorosilane. After 5 hoursof stirring the reaction mixture is evaporated and the remaining oil ischromatographed on a silica gel column eluting with ether. Theproduct-containing fractions are collected and the solvent is evaporatedleaving 1,1-difluorobutylphosphonous acid ethyl ester as colorless oil,Rf=0.4 (CH₂ Cl₂ /CH₃ COOH, 95+5).

280 mg (12 mMol) of sodium is dissolved in 17 ml of dry ethanol. Thissolution is cooled to -10° C. and 4.5 g (24.2 mMol) of1,1-difluorobutylphosphonous acid ethyl ester and 1.6 ml (24.2 mMol) ofacrylonitrile are added with stirring.

The reaction mixture is allowed to warm to room temperature and stirringis continued for 20 hours. The mixture is treated with glacial aceticacid and evaporated to dryness. The residue is dissolved indichloromethane, washed twice with water, dried with magnesium sulphateand evaporated, giving ethyl 2-cyanoethyl(1,1-difluorobutyl)phosphinateas an oil, Rf: 0.32 (CH₂ Cl₂ /CH₃ COO, 9+1).

3.2 g (13.4 mMol) of ethyl 2-cyanoethyl(1,1-difluorobutyl)phospinate aredissolved in 100 ml of dry ethanol and 10 g of liquid ammonia and 1 g ofRaney-nickel are added. This mixture is hydrogenated at 50° C. and 100bar hydrogen pressure for 3 hours.

The reaction mixture is filtered and the solvent removed under vacuum.After distillation of the oily the residue in a Kugelrohrofen at 130° Cand 2·10⁻³ mbar, there is obtained ethyl3-aminopropyl(1,1-difluorobutyl)phosphinate Rf: 0.22 (CH₂ Cl₂ /MeOH/NH₃90+9+1).

EXAMPLE 72

The solution of 2.4 g of ethyl3-phthalimido-2-trimethylsilyloxy-propyl(n-butyl)phosphinate in 50 ml ofconcentrated aqueous hydrochloric acid is heated to reflux for 20 hours.After this time the suspension is cooled to room temperature andfiltered. The filtrate is evaporated to dryness and the resultingsemi-solid is co-evaporated with water (5×50 ml) and absolute ethanol(5×100 ml) and the white solid dried in high vacuum overnight.Crystallisation from absolute ethanol affords3-amino-2-hydroxy-propyl(n-butyl)phosphinic acid hydrochloride, m.p.158-160°.

The starting material may be obtained as follows: A solution of 52.55 gof ethyl-1,1-diethoxyethylphosphinate in 50 ml of anhydroustetrahydrofuran is added dropwise to a suspension of 12 g of sodiumhydride (55% dispersion in oil) in 50 ml anhydrous tetrahydrofuran underan inert atmosphere maintaining the temperature at 15° C. After additionis complete, the resulting suspension is stirred for 1 hour at 20° C.before re-cooling to 15° and addition of 102.8 g n-butylbromide.

The suspension is stirred for 16 hours at 20° C. and water (50 ml) iscarefully added. After concentration in vacuo the residue is dissolvedin water/dichloromethane and extracted.

The organic layer is separated and dried with anhydrous magnesiumsulphate. Removal of the solvent in vacuo affords ethyl1,1-diethoxyethyl(n-butyl)phosphinate as a colourless oil.

A solution of 176 g of ethyl 1,1-diethoxyethyl(n-butyl)phosphinate in540 ml of absolute dichloromethane containing 10% of absolute ethanol istreated with 143.6 g of trimethylchlorosilane. After stirring for 48hours at room temperature, the solvent is removed in vacuo to afford apale yellow oil. Distillation in vacuo affords ethyln-butyl-phosphinate, b.p. 27-34° (2×10⁻² mbar).

A mixture of 3.79 g of anhydrous triethylamine and 4.5 g ethyln-butylphosphinate in 100 ml of anhydrous tetrahydrofuran under an inertatmosphere is treated with 4.07 g of trimethylchlorosilane. Theresulting suspension is stirred for 20 hours at room temperature and thesolid removed by filtration. Concentration in vacuo affords a cloudy,colourless oil which is treated with 6.09 g of anhydrousN-(2,3-epoxypropyl)phthalimide and 0.5 g of anhydrous zinc chloride. Themixture is heated to 66° C. under an inert atmosphere for 3 hours,cooled to 20° and diluted with dichloromethane. The organic solution iswashed with 100 ml 10% of aqueous sodium bicarbonate solution and driedover anhydrous magnesium sulphate. Removal of the solvent andchromatography on silica gel affords ethyl3-phthalimido-2-trimethylsilyloxy-propyl(n-butyl)phosphinate as aviscous oil.

EXAMPLE 73

A mixture of 1.23 g (10 mMol) of 3-aminopropylphosphonous acid and 8.07g (50 mMol) of hexamethyldisilazane is refluxed under an atmosphere ofargon with stirring for 16 hours to give a solution. To this solutionare added at reflux 5 ml of diethyleneglycol dimethyl ether and thereaction mixture is refluxed for additional 2 hours. The reactionmixture is then cooled to 100° and 1.94 g (15 mMol) ofN-ethyl-N,N-diisopropyl-amine is added during 10 minutes followed byaddition of 3.78 g (15 mMol) of 4,4,4-trifluoro-3-methyl-1-iodo-butane.The reaction mixture is heated with stirring at 150° for 22 hours. Aftercooling to 10°. the white precipitate is filtered off and the filtrateis evaporated under reduced pressure. The clear solution is cooled,diluted with dichlormethane (30 ml) and extracted with 2N hydrochloricacid (3×15 ml).

The combined hydrochloric acid extracts are evaporated in vacuo todryness and co-evaporated with water (2×15 ml) to give a white solidwhich is dissolved in 20 ml of methanol. Then 150 ml of propylene oxideare added. After standing overnight at 4°, a white solid precipitates.The precipitate is collected by filtration to give3-aminopropyl(4,4,4-trifluoro-3-methyl-butyl)phosphinic acid, m.p.245-250° (dec.)

The crude material is chromatographed on 35 g Opti-Up® C₁₂ eluting withwater. The product-containing fractions are collected and evaporated invacuo to dryness.

After recrystallisation from methanol diethylether give pure3-aminopropyl-(4,4,4-trifluoro-3-methyl-butyl)phosphinic acid of m.p.255-258° (dec.) 4,4,4-trifluoro-3-methyl-1-iodo-butane is prepared inthe following manner.

To a mixture of 19 g phosphoric acid (98%) and 19 g pottasium iodide areadded at 40° under stirring 4.75 g (33.4 mMol) of4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. Themixture is then heated at 120° for 16 hours, a cooling poured intoice-water and extracted with diethylether. The etheric extracts arewashed with 10% sodium thiosulfate and brine acid dried over sodiumsulphate. After filtration, the solvent is removed through a 15 cmVigreux-column at atmospheric pressure, followed by fractionation giving4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76-77° at 140 mbar.

EXAMPLE 74

In an analogous manner as described in Example 73, also3-aminopropyl(4,4,4-trifluoro-3-trifluoromethyl-butyl)phosphinic acidcan be manufactured.

EXAMPLE 75

A solution of 6.9 g of isobutyl3-amino-2-(4-chlorophenyl)propyl(methyl)phosphinate in 60 ml of 36%aqueous hydrochloric acid is heated to reflux for a period of 15 hours.The reaction mixture is allowed to cool to room temperature,concentrated under reduced pressure and co-evaporated three times with25 ml of water under reduced pressure. The crude product is dissolved in25 ml of water, washed twice with 20 ml of diethyl ether, and theaqueous layer treated with activated charcoal. The charcoal is removedby filtration and the filtrate evaporated under reduced pressure. Thecrude product is dissolved in 50 ml of ethanol and 2 ml of propyleneoxide are added dropwise. The precipitated solid is collected byfiltration when free from halogen and dried. Recrystallisation fromwater then give 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinic acidx1.0 H₂ O, m.p. 165-70°, ³¹ P N.M.R. spectrum: δ=+39.9 ppm (D₂ O).

The starting material may be prepared as follows:

To a solution of 1.62 g of diisopropylamine in 20 ml of drytetrahydrofuran at -78° C. under an atmosphere of nitrogen are added10.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution isthe stirred for a period of 10 minutes at this temperature, after whichtime a solution of 2.0 g of isobutyl, P,P-dimethyl-phosphinate is added.This mixture is stirred at -78° C. for a period of 1 hour, after whichtime a solution of 2.45 g of tran-1-(4-chlorophenyl)-2-nitro-ethene in20 ml of tetrahydrofuran is added. This mixture is then allowed to warmto room temperature when 40 ml of a saturated ammonium chloride solutionis added. The aqueous layer is then extracted with 2×25 ml of diethylether and the organic extracts are combined and dried over magnesiumsulphate. The solvent is then evaporated under reduced pressure and thecrude product purified by chromatography on silica gel using 5 partsethyl acetate to 1 part ethanol as eluent. The fractions containingproduct are combined and concentrated under reduced pressure to giveisobutyl 2-(4-chlorophenyl)-3-nitro-propyl-(methyl)phosphinate as aviscous oil; ³¹ P N.M.R. spectrum: δ=+50.5 and +50.1 ppm (CDCl₃).

A solution of 6.8 g of isobutyl2-(4-chlorophenyl)-3-nitro-propyl(methyl)phosphinate in 80 ml of ethanolis added to 64 g of an 8% solution of ammonia in ethanol. To this areadded 8 ml of Raney Nickel slurry and the resulting mixture ishydrogenated at 1 bar until hydrogen uptake ceases. The mixture is thenfiltered and the filtrate is concentrated under reduced pressure to giveisobutyl 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinate as aviscous oil, ³¹ P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl₃).

EXAMPLE 76

A solution of 11.8 g of isobutyl3-amino-2-(4-fluorophenyl)propyl-(methyl)phosphinate in 60 ml of 36%aqueous hydrochloric acid is heated to reflux for a period of 15 hours.The reaction mixture is allowed to cool to room temperature,concentrated under reduced pressure and co-evaporated three times with25 ml of water under reduced pressure. The crude product is dissolved in25 ml of water, washed twice with 20 ml of diethyl ether, and theaqueous layer treated with activated charcoal. The charcoal is removedby filtration and the filtrate evaporated under reduced pressure. Thecrude product is dissolved in 50 ml of ethanol and 1-2 ml of propyleneoxide is added dropwise. The precipitated solid is collected byfiltration when free from halogen and dried. Recrystallisation fromwater then give 3-amino-2-(4-fluorophenyl)-propyl(methyl)

phosphinic acid x1.0 H₂ O, m.p. 215-220°, ³¹ P N.M.R. spectrum: δ=+39.8ppm (D₂ O).

The starting material may be prepared as follows:

To a solution of 8.1 g of diisopropylamine in 50 ml of drytetrahydrofuran at -78° C. under an atmosphere of nitrogen are added50.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution isthen stirred for a period of 10 minutes at this temperature, after whichtime a solution of 10.0 g of isobutyl P,P-dimethyl-phosphinate is added.This mixture is stirred at -78° C. for a period of 1 hour, after whichtime a solution of 11.1 g of trans-1-(4-fluorophenyl)-2-nitro-ethene in50 ml of tetrahydrofuran is added. This mixture is then allowed to warmto room temperature when 40 ml of a saturated ammonium chloride solutionis added. The aqueous layer is then extracted with 2×25 ml of diethylether and the organic extracts are combined and dried over magnesiumsulphate. The solvent is then evaporated under reduced pressure and thecrude product purified by chromatography on silica gel using 5 partsethyl acetate to 1 part ethanol as eluent. The fractions containingproduct are combined and concentrated under reduced pressure to giveisobutyl 2-(4-fluorophenyl)-3-nitro-propyl-(methyl)phosphinate as aviscous oil, ³¹ P-N.M.R. spectrum: δ=+51.0 and +50.6 ppm (CDCl₃).

A solution of 11.6 g of isobutyl 2-(4-fluorophenyl)-3-nitro-propyl(methyl)phosphinate in 100 ml of ethanol is added to 114 g of a 8%solution of ammonia in ethanol. To this are added 9 ml of Raney Nickelslurry and the resulting mixture is hydrogenated at 1 bar until hydrogenuptake ceases. The mixture is then filtered and the filtrate isconcentrated under reduced pressure to give isobutyl3-amino-2-(4-fluorophenyl)-propyl-(methyl)phosphinate as a viscous oil,³¹ P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl₃).

EXAMPLE 77

A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml ofhexamethyldisilazane is heated to reflux under an inert gas for 24 hoursafter which a clear solution results. The excess hexamethyldisilazane isremoved by distillation at atmospheric pressure under a slight positivepressure of inert gas to afford a colourless oil. The oil is cooled tocirca 40° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of(S)-(+)-1,2-exoxy-3-methyl-butane. An exothermic reaction occurs and theepoxybutane refluxes. Reflux is continued for 6 hours after which timethin layer chromatography indicates the reaction to be complete. Thereaction mixture is filtered and the filtrate evaporated to dryness invacuo at 40°. The residue is dissolved in water and stirred at roomtemperature for 1 hour and the water removed in vacuo to give an oilysolid. This is dissolved in some 2.0 M aqueous hydrochloric acid andwashed with dichloromethane and ether. Removal of the water at 40° invacuo affords a brown solid which is purified by ion-exchancechromatography on DOWEX® 50 W x 8 (14-40 mesh) to give3-aminopropyl[2-(S)-hydroxy-3-methyl-butyl]phosphinic acid, m.p.187-189°, [α]²⁰ _(D) =-14.5°.

EXAMPLE 78

A solution of 0.64 g of ethyl3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl(methyl)phosphinate in 12 ml of concentrated aqueous hydrochloric acid is heated toreflux for 5 hours. The mixture is then cooled and evaporated to drynessin vacuo. The residue is repeatedly co-evaporated with methanol untilthe hydrochloride salt is obtained as a foam. This is dissolved in 50 mlof methanol and treated with 25 ml of propylene oxide after 40 minutesstirring at room temperature a solid precipitates, and the suspensionstirred for a further 11/2hours. The solid is collected by filtrationwashed with propylene oxide and ether and dried the solid is redissolvedin methanol at elevated temperature and filtered. Concentration in vacuoand dilution with ether affords a solid which is collected and dried togive 3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl(methyl)phosphinic acid,m.p. 240-241° C.

The starting material may be obtained as follows:

A solution of 1.46 g of3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde,0.54 g of ethyl methylphosphinate and 0.695 ml of triethylamine isheated to 100° for 2 hours. The reaction mixture is cooled to roomtemperature and chromatographed on silica gel to give ethyl3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxypropyl(methyl)phosphinate.

EXAMPLE 79

A solution of 0.35 g of ethyl3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl(n-butyl)phosphinic acid in 10 ml of 5.0 M aqueous hydrochloric acid is heated torefluxfor 24 hours. The reaction is cooled to room temperature andwashed with 3×50 ml dichloromethane and 1×50 ml ether. After evaporationof the aqueous layer the residue is co-evaporated with water (3×50 ml)and absolute ethanol (3×50 ml) and dried in high vacuum to afford3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl(n-bu yl)phosphinic acidhydrochloride.

The starting material may be prepared as follows:

A material of 283 mg of3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde,150 mg of ethyl n-butyl-phosphinate and 101 mg of triethylamine isheated to 100° C. for 21/2hours. The mixture is cooled to roomtemperature and the volatile components are removed in high vacuum.Chromatography of the residue on silica-gel affords ethyl3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl-(nbutyl)phosphinate.

EXAMPLE 80

Preparation of 10,000 tablets each containing 100 mg of the activeingredient with a formula as follows:

    ______________________________________                                        3-amino-2-hydroxy-propyl(diethoxy-                                                                 1,000.00 g                                               methyl)phosphinic acid                                                        Lactose              257.00 g                                                 Corn starch          75.00 g                                                  Polyethylene glycol 6,000                                                                          75.00 g                                                  Magnesium stearate   18.00 g                                                  Purified water       q.s.                                                     ______________________________________                                    

Procedure: All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 40 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 150 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1,2 mm openings and compressed into tablets with12.8 mm diameter, uppers bisected.

EXAMPLE 81

Preparation of 10,000 capsules each containing 25 mg of the activeingredient with a formula as follows:

    ______________________________________                                        3-amino-2-hydroxypropyl(diethoxy-                                                                     250.0 g                                               methyl)phosphinic acid                                                        Lactose               1,750.0 g                                               ______________________________________                                    

Procedure: All the powders are passed through a screen with openings of0.6 mm. Then the drug substance is placed in a suitable mixer and mixedwith the lactose until homogenous. No. 3 capsules are filled with 200 mgusing a capsule filling machine.

EXAMPLE 82

In a manner analogous to that described in Examples 82 and 81

tablets and capsules comprising as the active ingredients 10-100 mg ofanother compounds of the invention, e.g. as described in the Examples 1to 79.

What is claimed is:
 1. A process for the manufacture of a compound offormula I ##STR35## wherein R denotes an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbonatoms, and wherein one of the groups R¹, R² and R³ represents hydrogenor an aliphatic, cycloaliphatic, araliphatic or aromatic radical,another one of the groups R¹, R² and R³ is hydrogen or in the case of R¹and R², is hydroxy, and the remaining one of R¹, R² and R³ is hydrogen,and salts thereof, wherein a compound of the formula XIV ##STR36##wherein R⁵ _(b) denotes a C₁ -C₄ alkyl radical, X denotes cyano orcarbamoyl and Q' denotes a group of the formula --C(OR⁸)(OR⁹)(OR¹⁰)(XIVa) in which R⁸ represents hydrogen or lower alkyl and R⁹ and R¹⁰,independently of each other, represent lower alklyl or togetherrepresent lower alkylene and R¹ and R² are defined hereinabove, istreated with trimethylsilylchloride in technical chloroform thatcontains ethanol, resulting in a compound of the formula XV ##STR37##wherein R¹, R², R⁵ _(b) and X are defined hereinabove, which compound isreacted with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic oraraliphatic aldehyde or ketone of the formula (R')(R")C=O (XIIa) or witha compound of the formulae R"'--CH=CH₂ (XIIb) or R-Hal (XIIc), whereinR' denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic oraraliphatic hydrocarbon radical, R" represents hydrogen or an aliphatichydrocarbon radical, R"' denotes an aliphatic, cycloaliphatic oraromatic group and R is defined hereinabove, resulting in a compound ofthe formula VI ##STR38## wherein R¹, R², R⁵ _(b) R and X are definedhereinabove, the cyano or carbamoyl group X is reduced to a group of theformula --CH₂ NH₂, resulting in a compound of the formula IIa ##STR39##wherein R, R¹, R², R³ and R⁵ _(b) are defined hereinabove, whichcompound is converted into the corresponding compound of the formula Iand, if a free compound is required, the resulting salt is convertedinto the free compound or, if a salt is required, the resulting freecompound is converted into a salt and, if an individual isomer isrequired, the resulting mixture of isomers is separated into theindividual isomers.
 2. A process for the manufacture of a compound ofthe formula I ##STR40## wherein R denotes an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbonatoms, and wherein one of the groups R¹, R² and R³ represents hydrogenor an aliphatic, cycloaliphatic, araliphatic or aromatic radical,another one of the groups R¹, R² and R³ is hydrogen or in the case of R¹and R² is hydroxy, and the remaining one of R¹, R² and R³ is hydrogen,and salts thereof, wherein a compound of the formula XIV ##STR41##wherein R⁵ _(b) denotes a C₁ -C₄ alkyl radical, X denotes a group of theformula --CH(R³)--Z^(o) (XVa) in which Z^(o) represents a protectedamino group and Q' denotes a group of the formula--C(OR⁸)(OR⁹)(OR¹⁰)(XIVa) in which R⁸ denotes hydrogen or lower alkyland R⁹ and R¹⁰, independently of each other, represent lower alkyl ortogether represent lower alkylene and R¹ and R² are defined hereinabove,which compound is treated with trimethylsilylchloride in technicalchloroform that contains ethanol, resulting in a compound of the formulaXV ##STR42## wherein R¹, R², R⁵ _(b) and X are defined hereinabove,which compound is reacted with an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic aldehyde or ketone of theformula (R')(R")C=O(XIIa) or with a compound of the formula R"'--CH=CH₂(XIIb) or R-Hal (XIIc), wherein R' denotes an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, R"represents hydrogen or an aliphatic hydrocarbon radical, R"' denotes analiphatic, cycloaliphatic or aromatic group and R is definedhereinabove, resulting in a compound of the formula VI ##STR43## whereinR¹, R², R⁵ _(b), R and X are defined hereinabove, and wherein in thegroup of the formula --CH(R³)--Z^(o) (XVa)Z^(o) denotes protected amino,the group Z^(o) is converted into amino resulting in a compound of theformula IIa ##STR44## wherein R, R¹, R², R³ and R⁵ _(b) are definedhereinabove, which compound is converted into the corresponding compoundof the formula I and, if a free compound is required, a resulting saltis converted into the free compound or, if a salt is required, aresulting free compound is converted into a salt and, if an individualisomer is required, a resulting mixture of isomers is separated into theindividual isomers.
 3. A process for the manufacture of a compound ofthe formula I ##STR45## wherein R denotes an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbonatoms, and wherein one of the groups R¹, R² and R³ represents hydrogenor an aliphatic, cycloaliphatic, araliphatic or aromatic radical,another one of the groups R¹, R² and R³ is hydrogen or in the case of R¹and R² is hydroxy, and the remaining one of R¹, R² and R³ is hydrogen,and salts thereof, wherein a compound of the formula XIV ##STR46##wherein R⁵ _(b) denotes a C₁ -C₄ alkyl radical, X denotes a group of theformula --CH(R³)--Z^(o) (XVa) in which Z^(o) represents a nitro or azidogroup and Q' denotes a group of the formula --C(OR⁸)(OR⁹)(OR¹⁰) (XIVa)in which R⁸ denotes hydrogen or lower alkyl and R⁹ and R¹⁰,independently of each other, represent lower alkyl or together representlower alkylene and R¹, R² and R³ are defined hereinabove, is treatedwith trimethylsilylchloride in technical chloroform that containsethanol, resulting in a compound of the formula XV ##STR47## wherein R¹,R², R⁵ _(b) and X are defined hereinabove, which compound is reactedwith an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic oraraliphatic aldehyde or ketone of the formula (R')(R")C=O (XIIa) or witha compound of the formula R"'--CH=CH₂ (XIIb) or R-Hal (XIIc), wherein R'denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic oraraliphatic hydrocarbon radical, R" represents hydrogen or an aliphatichydrocarbon radical, R"' denotes an aliphatic, cycloaliphatic oraromatic group and R is defined hereinabove, resulting in a compound ofthe formula VI ##STR48## wherein R¹, R², R⁵ _(b), R and X are definedhereinabove and wherein in the group of the formula --CH(R³)--Z^(o)(XVa) in which Z^(o) denotes nitro or azido, Z^(o) is reduced to aminoresulting in a compound of the formula IIa ##STR49## wherein R, R¹, R²,R³ and R⁵ _(b) are defined hereinabove, which compound is converted intothe corresponding compound of the formula I and, if a free compound isrequired, a resulting salt is converted into the free compound or, if asalt is required, a resulting free compound is converted into a saltand, if an individual isomer is required, a resulting mixture of isomersis separated into the individual isomers.
 4. A process for themanufacture of a compound of the formula I ##STR50## wherein r denotesan aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphaticradical having 2 or more carbon atoms, and wherein one of the groups R¹,R² and R³ represents hydrogen or an aliphatic, cycloaliphatic,araliphatic or aromatic radical, another one of the groups R¹, R² and R³is hydrogen or in the case of R¹ and R², is hydroxy, and the remainingone of R¹, R² and R³ is hydrogen, and salts thereof, wherein a compoundof the formula XIV ##STR51## wherein R⁵ _(b) denotes a C₁ -C₄ alkylradical, X denotes a group of the formula --C(R³)=Y (XVb) in which Yrepresents an optionally acetalized, thioacetalized, ketalized orthioketalized oxo group and Q' denotes a group of the formula--C(OR⁸)(OR⁹)(OR¹⁰) (XIVa) in which R⁸ denotes hydrogen or lower alkyland R⁹ and R¹⁰, independently of each other, represent lower alkyl ortogether represent lower alkylene and R¹, R² and R³ are definedhereinabove, is treated with trimethylsilylchloride in technicalchloroform that contains ethanol, resulting in a compound of the formulaXV ##STR52## wherein R¹, R², R⁵ _(b) and X are defined hereinabove,which compound is reacted with an aliphatic,cycloaliphatic,cycloaliphatic-aliphatic or araliphatic aldehyde orketone of the formula (')(R")C=O (XIIa) or with a compound of theformulae R"'--CH=CH₂ (XIIb) or R-Hal (XIIc), wherein R' denotes analiphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatichydrocarbon radical and R" represents hydrogen or an aliphatichydrocarbon radical, R"' denotes an aliphatic, cycloaliphatic oraromatic group and R is defined hereinabove, resulting in a compound ofthe formula VI ##STR53## wherein R¹, R², R⁵ _(b), R and X are definedhereinabove, the group of the formula --C(R³)=Y (XVb) is reductivelyaminated, resulting in a compound of the formula IIa ##STR54## whereinR, R¹, R², R³ and R⁵ _(b) are defined hereinabove, which compound isconverted into the corresponding compound of the formula I and, if afree compound is required, a resulting salt is converted into the freecompound or, if a salt is required, a resulting free compound isconverted into a salt and, if an individual isomer is required, aresulting mixture of isomers is separated into the individual isomers.